Salts of an lsd1 inhibitor and processes for preparing the same

ABSTRACT

The present invention relates to processes and intermediates for preparing 3-(cyanomethyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamide, and salts and solid forms thereof, which selectively modulate demethylase. Particular embodiments contemplate compounds and disease indications amenable to treatment by modulation of lysine specific demethylase-1 (LSD1).

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims the benefit of U.S. ProvisionalApplication No. 62/725,961, filed Aug. 31, 2018, which is incorporatedherein by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to processes and intermediates forpreparing3-(cyanomethyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamide,and salts thereof, which selectively modulate demethylase. The presentinvention is further directed to solid forms of3-(cyanomethyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamideand its salts, and hydrates and solvates thereof. The compounds andsalts, solvates, and hydrates thereof as described herein are useful inthe treatment of LSD1 diseases.

BACKGROUND OF THE INVENTION

Epigenetic modifications can impact genetic variation but, whendysregulated, can also contribute to the development of various diseases(Portela, A. and M. Esteller, Epigenetic modifications anda3 humandisease. Nat Biotechnol, 2010. 28(10): p. 1057-68; Lund, A. H. and M.van Lohuizen, Epigenetics and cancer. Genes Dev, 2004. 18(19): p.2315-35). Recently, in depth cancer genomics studies have discoveredmany epigenetic regulatory genes are often mutated or their ownexpression is abnormal in a variety of cancers (Dawson, M. A. and T.Kouzarides, Cancer epigenetics: from mechanism to therapy. Cell, 2012.150(1): p. 12-27; Waldmann, T. and R. Schneider, Targeting histonemodifications—epigenetics in cancer. Curr Opin Cell Biol, 2013. 25(2):p. 184-9; Shen, H. and P. W. Laird, Interplay between the cancer genomeand epigenome. Cell, 2013. 153(1): p. 38-55). This implies epigeneticregulators function as cancer drivers or are permissive fortumorigenesis or disease progression. Therefore, deregulated epigeneticregulators are attractive therapeutic targets.

One particular enzyme which is associated with human diseases is lysinespecific demethylase-1 (LSD1), the first discovered histone demethylase(Shi, Y., et al., Histone demethylation mediated by the nuclear amineoxidase homolog LSD1. Cell, 2004. 119(7): p. 941-53). It consists ofthree major domains: the N-terminal SWIRM which functions in nucleosometargeting, the tower domain which is involved in protein-proteininteraction, such as transcriptional co-repressor, co-repressor ofRE1-silencing transcription factor (CoREST), and lastly the C terminalcatalytic domain whose sequence and structure share homology with theflavin adenine dinucleotide (FAD)-dependent monoamine oxidases (i.e.,MAO-A and MAO-B) (Forneris, F., et al., Structural basis of LSD1-CoRESTselectivity in histone H3 recognition. J Biol Chem, 2007. 282(28): p.20070-4; Anand, R. and R. Marmorstein, Structure and mechanism oflysine-specific demethylase enzymes. J Biol Chem, 2007. 282(49): p.35425-9; Stavropoulos, P., G. Blobel, and A. Hoelz, Crystal structureand mechanism of human lysine-specific demethylase-1. Nat Struct MolBiol, 2006. 13(7): p. 626-32; Chen, Y., et al., Crystal structure ofhuman histone lysine-specific demethylase 1 (LSD1). Proc Natl Acad SciUSA, 2006. 103(38): p. 13956-61). LSD1 also shares a fair degree ofhomology with another lysine specific demethylase (LSD2) (Karytinos, A.,et al., A novel mammalian flavin-dependent histone demethylase. J BiolChem, 2009. 284(26): p. 17775-82). Although the biochemical mechanism ofaction is conserved in two isoforms, the substrate specificities arethought to be distinct with relatively small overlap. The enzymaticreactions of LSD1 and LSD2 are dependent on the redox process of FAD andthe requirement of a protonated nitrogen in the methylated lysine isthought to limit the activity of LSD1/2 to mono- and di-methylated atthe position of 4 or 9 of histone 3 (H3K4 or H3K9). These mechanismsmake LSD1/2 distinct from other histone demethylase families (i.e.Jumonji domain containing family) that can demethylate mono-, di-, andtri-methylated lysines through alpha-ketoglutarate dependent reactions(Kooistra, S. M. and K. Helin, Molecular mechanisms and potentialfunctions of histone demethylases. Nat Rev Mol Cell Biol, 2012. 13(5):p. 297-311; Mosammaparast, N. and Y. Shi, Reversal of histonemethylation: biochemical and molecular mechanisms of histonedemethylases. Annu Rev Biochem, 2010. 79: p. 155-79).

Methylated histone marks on K3K4 and H3K9 are generally coupled withtranscriptional activation and repression, respectively. As part ofcorepressor complexes (e.g., CoREST), LSD1 has been reported todemethylate H3K4 and repress transcription, whereas LSD1, in nuclearhormone receptor complex (e.g., androgen receptor), may demethylate H3K9to activate gene expression (Metzger, E., et al., LSD1 demethylatesrepressive histone marks to promote androgen-receptor-dependenttranscription. Nature, 2005. 437(7057): p. 436-9; Kahl, P., et al.,Androgen receptor coactivators lysine-specific histone demethylase 1 andfour and a half LIM domain protein 2 predict risk of prostate cancerrecurrence. Cancer Res, 2006. 66(23): p. 11341-7). This suggests thesubstrate specificity of LSD1 can be determined by associated factors,thereby regulating alternative gene expressions in a context dependentmanner. In addition to histone proteins, LSD1 may demethylatenon-histone proteins. These include p53 (Huang, J., et al., p53 isregulated by the lysine demethylase LSD1. Nature, 2007. 449(7158): p.105-8.), E2F (Kontaki, H. and I. Talianidis, Lysine methylationregulates E2F1-induced cell death. Mol Cell, 2010. 39(1): p. 152-60),STAT3 (Yang, J., et al., Reversible methylation of promoter-bound STAT3by histone-modifying enzymes. Proc Natl Acad Sci USA, 2010. 107(50): p.21499-504), Tat (Sakane, N., et al., Activation of HIV transcription bythe viral Tat protein requires a demethylation step mediated bylysine-specific demethylase 1 (LSD1/KDM1). PLoS Pathog, 2011. 7(8): p.e1002184), and myosin phosphatase target subunit 1 (MYPT1) (Cho, H. S.,et al., Demethylation of RB regulator MYPT1 by histone demethylase LSD1promotes cell cycle progression in cancer cells. Cancer Res, 2011.71(3): p. 655-60). The lists of non-histone substrates are growing withtechnical advances in functional proteomics studies. These suggestadditional oncogenic roles of LSD1 beyond in regulating chromatinremodeling. LSD1 also associates with other epigenetic regulators, suchas DNA methyltransferase 1 (DNMT1) (Wang, J., et al., The lysinedemethylase LSD1 (KDM1) is required for maintenance of global DNAmethylation. Nat Genet, 2009. 41(1): p. 125-9) and histone deacetylases(HDACs) complexes (Hakimi, M. A., et al., A core-BRAF35 complexcontaining histone deacetylase mediates repression of neuronal-specificgenes. Proc Natl Acad Sci USA, 2002. 99(11): p. 7420-5; Lee, M. G., etal., Functional interplay between histone demethylase and deacetylaseenzymes. Mol Cell Biol, 2006. 26(17): p. 6395-402; You, A., et al.,CoREST is an integral component of the CoREST-human histone deacetylasecomplex. Proc Natl Acad Sci USA, 2001. 98(4): p. 1454-8). Theseassociations augment the activities of DNMT or HDACs. LSD1 inhibitorsmay therefore potentiate the effects of HDAC or DNMT inhibitors. Indeed,preclinical studies have shown such potential already (Singh, M. M., etal., Inhibition of LSD1 sensitizes glioblastoma cells to histonedeacetylase inhibitors. Neuro Oncol, 2011. 13(8): p. 894-903; Han, H.,et al., Synergistic re-activation of epigenetically silenced genes bycombinatorial inhibition of DNMTs and LSD1 in cancer cells. PLoS One,2013. 8(9): p. e75136).

LSD1 has been reported to contribute to a variety of biologicalprocesses, including cell proliferation, epithelial-mesenchymaltransition (EMT), and stem cell biology (both embryonic stem cells andcancer stem cells) or self-renewal and cellular transformation ofsomatic cells (Chen, Y., et al., Lysine-specific histone demethylase 1(LSD1): A potential molecular target for tumor therapy. Crit RevEukaryot Gene Expr, 2012. 22(1): p. 53-9; Sun, G., et al., Histonedemethylase LSD1 regulates neural stem cell proliferation. Mol CellBiol, 2010. 30(8): p. 1997-2005; Adamo, A., M. J. Barrero, and J. C.Izpisua Belmonte, LSD1 and pluripotency: a new player in the network.Cell Cycle, 2011. 10(19): p. 3215-6; Adamo, A., et al., LSD1 regulatesthe balance between self-renewal and differentiation in human embryonicstem cells. Nat Cell Biol, 2011. 13(6): p. 652-9). In particular, cancerstem cells or cancer initiating cells have some pluripotent stem cellproperties that contribute the heterogeneity of cancer cells. Thisfeature may render cancer cells more resistant to conventionaltherapies, such as chemotherapy or radiotherapy, and then developrecurrence after treatment (Clevers, H., The cancer stem cell: premises,promises and challenges. Nat Med, 2011. 17(3): p. 313-9; Beck, B. and C.Blanpain, Unravelling cancer stem cell potential. Nat Rev Cancer, 2013.13(10): p. 727-38). LSD1 was reported to maintain an undifferentiatedtumor initiating or cancer stem cell phenotype in a spectrum of cancers(Zhang, X., et al., Pluripotent Stem Cell Protein Sox2 ConfersSensitivity to LSD1 Inhibition in Cancer Cells. Cell Rep, 2013. 5(2): p.445-57; Wang, J., et al., Novel histone demethylase LSD1 inhibitorsselectively target cancer cells with pluripotent stem cell properties.Cancer Res, 2011. 71(23): p. 7238-49). Acute myeloid leukemias (AMLs)are an example of neoplastic cells that retain some of their lessdifferentiated stem cell like phenotype or leukemia stem cell (LSC)potential. Analysis of AML cells including gene expression arrays andchromatin immunoprecipitation with next generation sequencing (ChIP-Seq)revealed that LSD1 may regulate a subset of genes involved in multipleoncogenic programs to maintain LSC (Harris, W. J., et al., The histonedemethylase KDM1A sustains the oncogenic potential of MLL-AF9 leukemiastem cells. Cancer Cell, 2012. 21(4): p. 473-87; Schenk, T., et al.,Inhibition of the LSD1 (KDM1A) demethylase reactivates theall-trans-retinoic acid differentiation pathway in acute myeloidleukemia. Nat Med, 2012. 18(4): p. 605-11). These findings suggestpotential therapeutic benefit of LSD1 inhibitors targeting cancershaving stem cell properties, such as AMLs.

Overexpression of LSD1 is frequently observed in many types of cancers,including bladder cancer, NSCLC, breast carcinomas, ovary cancer,glioma, colorectal cancer, sarcoma including chondrosarcoma, Ewing'ssarcoma, osteosarcoma, and rhabdomyosarcoma, neuroblastoma, prostatecancer, esophageal squamous cell carcinoma, and papillary thyroidcarcinoma. Notably, studies found over-expression of LSD1 wassignificantly associated with clinically aggressive cancers, forexample, recurrent prostate cancer, NSCLC, glioma, breast, colon cancer,ovary cancer, esophageal squamous cell carcinoma, and neuroblastoma. Inthese studies, either knockdown of LSD1 expression or treatment withsmall molecular inhibitors of LSD1 resulted in decreased cancer cellproliferation and/or induction of apoptosis. See, e.g., Hayami, S., etal., Overexpression of LSD1 contributes to human carcinogenesis throughchromatin regulation in various cancers. Int J Cancer, 2011. 128(3): p.574-86; Lv, T., et al., Over-expression of LSD1 promotes proliferation,migration and invasion in non-small cell lung cancer. PLoS One, 2012.7(4): p. e35065; Serce, N., et al., Elevated expression of LSD1(Lysine-specific demethylase 1) during tumour progression frompre-invasive to invasive ductal carcinoma of the breast. BMC ClinPathol, 2012. 12: p. 13; Lim, S., et al., Lysine-specific demethylase 1(LSD1) is highly expressed in ER-negative breast cancers and a biomarkerpredicting aggressive biology. Carcinogenesis, 2010. 31(3): p. 512-20;Konovalov, S. and I. Garcia-Bassets, Analysis of the levels oflysine-specific demethylase 1 (LSD1) mRNA in human ovarian tumors andthe effects of chemical LSD1 inhibitors in ovarian cancer cell lines. JOvarian Res, 2013. 6(1): p. 75; Sareddy, G. R., et al., KDM1 is a noveltherapeutic target for the treatment of gliomas. Oncotarget, 2013. 4(1):p. 18-28; Ding, J., et al., LSD1-mediated epigenetic modificationcontributes to proliferation and metastasis of colon cancer. Br JCancer, 2013. 109(4): p. 994-1003; Bennani-Baiti, I. M., et al.,Lysine-specific demethylase 1 (LSD1/KDM1A/AOF2/BHC110) is expressed andis an epigenetic drug target in chondrosarcoma, Ewing's sarcoma,osteosarcoma, and rhabdomyosarcoma. Hum Pathol, 2012. 43(8): p. 1300-7;Schulte, J. H., et al., Lysine-specific demethylase 1 is stronglyexpressed in poorly differentiated neuroblastoma: implications fortherapy. Cancer Res, 2009. 69(5): p. 2065-71; Crea, F., et al., Theemerging role of histone lysine demethylases in prostate cancer. MolCancer, 2012. 11: p. 52; Suikki, H. E., et al., Genetic alterations andchanges in expression of histone demethylases in prostate cancer.Prostate, 2010. 70(8): p. 889-98; Yu, Y., et al., High expression oflysine-specific demethylase 1 correlates with poor prognosis of patientswith esophageal squamous cell carcinoma. Biochem Biophys Res Commun,2013. 437(2): p. 192-8; Kong, L., et al., Immunohistochemical expressionof RBP2 and LSD1 in papillary thyroid carcinoma. Rom J Morphol Embryol,2013. 54(3): p. 499-503.

Recently, the induction of CD86 expression by inhibiting LSD1 activitywas reported (Lynch, J. T., et al., CD86 expression as a surrogatecellular biomarker for pharmacological inhibition of the histonedemethylase lysine-specific demethylase 1. Anal Biochem, 2013. 442(1):p. 104-6). CD86 expression is a marker of maturation of dendritic cells(DCs) which are involved in antitumor immune response. Notably, CD86functions as a co-stimulatory factor to activate T cell proliferation(Greaves, P. and J. G. Gribben, The role of B7 family molecules inhematologic malignancy. Blood, 2013. 121(5): p. 734-44; Chen, L. and D.B. Flies, Molecular mechanisms of T cell co-stimulation andco-inhibition. Nat Rev Immunol, 2013. 13(4): p. 227-42).

In addition to playing a role in cancer, LSD1 activity has also beenassociated with viral pathogenesis. Particularly, LSD1 activity appearsto be linked with viral replications and expressions of viral genes. Forexample, LSD1 functions as a co-activator to induce gene expression fromthe viral immediate early genes of various type of herpes virusincluding herpes simplex virus (HSV), varicella zoster virus (VZV), andβ-herpesvirus human cytomegalovirus (Liang, Y., et al., Targeting theJMJD2 histone demethylases to epigenetically control herpesvirusinfection and reactivation from latency. Sci Transl Med, 2013. 5(167):p. 167ra5; Liang, Y., et al., Inhibition of the histone demethylase LSD1blocks alpha-herpesvirus lytic replication and reactivation fromlatency. Nat Med, 2009. 15(11): p. 1312-7). In this setting, a LSD1inhibitor showed antiviral activity by blocking viral replication andaltering virus associated gene expression.

Recent studies have also shown that the inhibition of LSD1 by eithergenetic depletion or pharmacological intervention increased fetal globingene expression in erythroid cells (Shi, L., et al., Lysine-specificdemethylase 1 is a therapeutic target for fetal hemoglobin induction.Nat Med, 2013. 19(3): p. 291-4; Xu, J., et al., Corepressor-dependentsilencing of fetal hemoglobin expression by BCL11A. Proc Natl Acad SciUSA, 2013. 110(16): p. 6518-23). Inducing fetal globin gene would bepotentially therapeutically beneficial for the disease ofβ-globinopathies, including β-thalassemia and sickle cell disease wherethe production of normal β-globin, a component of adult hemoglobin, isimpaired (Sankaran, V. G. and S. H. Orkin, The switch from fetal toadult hemoglobin. Cold Spring Harb Perspect Med, 2013. 3(1): p. a011643;Bauer, D. E., S. C. Kamran, and S. H. Orkin, Reawakening fetalhemoglobin: prospects for new therapies for the beta-globin disorders.Blood, 2012. 120(15): p. 2945-53). Moreover, LSD1 inhibition maypotentiate other clinically used therapies, such as hydroxyurea orazacitidine. These agents may act, at least in part, by increasingγ-globin gene expression through different mechanisms.

In summary, LSD1 contributes to tumor development by altering epigeneticmarks on histones and non-histone proteins. Accumulating data havevalidated that either genetic depletion or pharmacological interventionof LSD1 normalizes altered gene expressions, thereby inducingdifferentiation programs into mature cell types, decreasing cellproliferation, and promoting apoptosis in cancer cells. Therefore, LSD1inhibitors alone or in combination with established therapeutic drugswould be effective to treat the diseases associated with LSD1 activity.

SUMMARY OF THE INVENTION

The present disclosure provides, inter alia, salts of3-(cyanomethyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamide(Compound 1):

or a hydrate or solvate thereof. The present disclosure also providesprocesses and intermediates for preparing Compound 1 and its salts.

Provided herein are solid forms of Compound 1 and its salts.

The present disclosure is further directed to the hydrochloric acid saltof Compound 1 (e.g., the mono-hydrochloric acid salt of Compound 1 orthe di-hydrochloric acid salt of Compound 1), methanesulfonic acid saltof Compound 1 (e.g., the mono-methanesulfonic acid salt of Compound 1 orthe di-methanesulfonic acid salt of Compound 1), malonic acid salt ofCompound 1, ethanesulfonic acid salt of Compound 1, maleic acid salt ofCompound 1, camphorsulfonic acid salt of Compound 1, isethionic acidsalt of Compound 1, and the 1,2-ethanedisulfonic acid salt of Compound1.

The present disclosure is further directed to crystalline forms of thesalts described herein.

Provided herein are also pharmaceutical compositions, which includeCompound 1 and its salts, and solid forms thereof as described herein,and one or more pharmaceutically acceptable carriers or excipients.

The present disclosure also provides methods of inhibiting LSD1 enzymesusing Compound 1 and its salts, and solid forms thereof as describedherein.

The present disclosure also provides therapeutic methods of usingCompound 1 and its salts, and solid forms thereof as described herein.The present disclosure also provides uses of Compound 1 and its salts,and solid forms thereof as described herein in the manufacture of amedicament for use in therapy. The present disclosure also Compound 1and its salts, and solid forms thereof as described herein for use intherapy.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows an X-ray powder diffraction (XRPD) pattern of Compound 1di-HCl, Form I.

FIG. 2 shows a differential scanning calorimetry (DSC) thermogram ofCompound 1 di-HCl, Form I.

FIG. 3 shows a thermogravimetric analysis (TGA) thermogram of Compound 1di-HCl, Form I.

FIG. 4 shows an XRPD pattern of Compound 1 di-HCl, Form II.

FIG. 5 shows a DSC thermogram of Compound 1 di-HCl, Form II.

FIG. 6 shows a TGA thermogram of Compound 1 di-HCl, Form II.

FIG. 7 shows an XRPD pattern of Compound 1 di-HCl, Form III.

FIG. 8 shows an XRPD pattern of Compound 1 di-HCl, Form IV.

FIG. 9 shows an XRPD pattern of Compound 1 di-HCl, Form V.

FIG. 10 shows a DSC thermogram of Compound 1 di-HCl, Form V.

FIG. 11 shows a TGA thermogram of Compound 1 di-HCl, Form V.

FIG. 12 shows an XRPD pattern of Compound 1 di-mesylate.

FIG. 13 shows a DSC thermogram of Compound 1 di-mesylate.

FIG. 14 shows a TGA thermogram of Compound 1 di-mesylate.

FIG. 15 shows an XRPD pattern of Compound 1 malonate.

FIG. 16 shows a DSC thermogram of Compound 1 malonate.

FIG. 17 shows a TGA thermogram of Compound 1 malonate.

FIG. 18 shows an XRPD pattern of Compound 1 mono-HCl.

FIG. 19 shows a DSC thermogram of Compound 1 mono-HCl.

FIG. 20 shows a TGA thermogram of Compound 1 mono-HCl.

FIG. 21 shows an XRPD pattern of Compound 1 esylate.

FIG. 22 shows a DSC thermogram of Compound 1 esylate.

FIG. 23 shows a TGA thermogram of Compound 1 esylate.

FIG. 24 shows an XRPD pattern of Compound 1 maleate.

FIG. 25 shows a DSC thermogram of Compound 1 maleate.

FIG. 26 shows a TGA thermogram of Compound 1 maleate.

FIG. 27 shows an XRPD pattern of Compound 1 camsylate.

FIG. 28 shows a DSC thermogram of Compound 1 camsylate.

FIG. 29 shows a TGA thermogram of Compound 1 camsylate.

FIG. 30 shows an XRPD pattern of Compound 1 isethionate.

FIG. 31 shows a DSC thermogram of Compound 1 isethionate.

FIG. 32 shows a TGA thermogram of Compound 1 isethionate.

FIG. 33 shows an XRPD pattern of Compound 1 1,2-ethanedisulfonate.

FIG. 34 shows a DSC thermogram of Compound 1 1,2-ethanedisulfonate.

FIG. 35 shows an XRPD pattern of Compound 1 mono-mesylate.

FIG. 36 shows a DSC thermogram of Compound 1 mono-mesylate.

FIG. 37 shows an XRPD pattern of Compound 1 (free base).

FIG. 38 shows a DSC thermogram of Compound 1 (free base).

FIG. 39 shows a TGA thermogram of Compound 1 (free base).

DETAILED DESCRIPTION

This disclosure provides salts of an LSD-1 inhibitor and processes andintermediates for preparing the same. LSD-1 inhibitors are described inU.S. Pat. No. 9,493,450, filed Feb. 2, 2015, which is incorporatedherein by reference in its entirety, including3-(cyanomethyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamide,which is depicted below as Compound 1.

Provided herein is an acid salt of Compound 1, or a hydrate or solvatethereof. The salt can be substantially crystalline. In some embodiments,the salt is a solid form. In some embodiments, the salt is crystalline.

In some embodiments, the acid is selected from hydrochloric acid,methanesulfonic acid, malonic acid, ethanesulfonic acid, maleic acid,camphorsulfonic acid, the isethionic acid, 1,2-ethanedisulfonic acid,and methanesulfonic acid.

In some embodiments, the salt of Compound 1 is a hydrochloric acid salt.In some embodiments, the salt of Compound 1 is a di-hydrochloric acidsalt. The di-hydrochloric acid salt can be represented by its chemicalname:3-(cyanomethyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamidedihydrochloride; or3-(cyanomethyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamidedi-hydrochloric acid salt. The dihydrochloric acid salt of Compound 1 isreferred to herein as “Compound 1 di-HCl,” and “Compound 1di-hydrochloride.” In some embodiments, the dihydrochloric acid salt hasForm I, Form II, Form III, Form IV, or Form V. In some embodiments, thesalt of Compound 1 is a mono-hydrochloric acid salt. Themono-hydrochloric acid salt can be represented by its chemical name:3-(cyanomethyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamidehydrochloride; or 3-(cyanomethyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamidemono-hydrochloric acid salt. The mono-hydrochloric acid salt of Compound1 is referred to herein as “Compound 1 HCl” or “Compound 1 mono-HCl.”

In some embodiments, the salt of Compound 1 is a di-methanesulfonic acidsalt. The di-methanesulfonic acid salt can be represented by itschemical name:3-(cyanomethyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamidedimesylate; or3-(cyanomethyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamidedi-methanesulfonic acid salt. The di-methanesulfonic acid salt ofCompound 1 is referred to herein as “Compound 1 di-mesylate.” In someembodiments, the salt of Compound 1 is a mono-methanesulfonic acid salt.The mono-methanesulfonic acid salt can be represented by its chemicalname:3-(cyanomethyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamidemesylate; or3-(cyanomethyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamidemono-methanesulfonic acid salt. The methanesulfonic acid salt ofCompound 1 is referred to herein as “Compound 1 mesylate” or “Compound 1mono-mesylate.”

In some embodiments, the salt of Compound 1 is a malonic acid salt. Themalonic acid salt can be represented by its chemical name:3-(cyanomethyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamidemalonate; or3-(cyanomethyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamidemono-malonic acid salt. The malonic acid salt of Compound 1 is referredto herein as “Compound 1 malonate.”

In some embodiments, the salt of Compound 1 is an ethanesulfonic acidsalt. The ethanesulfonic acid salt can be represented by its chemicalname:3-(cyanomethyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamideesylate; or3-(cyanomethyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamidemono-ethanesulfonic acid salt. The ethanesulfonic acid salt of Compound1 is referred to herein as “Compound 1 esylate.”

In some embodiments, the salt of Compound 1 is a maleic acid salt. Themaleic acid salt can be represented by its chemical name:3-(cyanomethyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamidemaleate; or3-(cyanomethyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamidemono-maleic acid salt. The maleic acid salt of Compound 1 is referred toherein as “Compound 1 maleate.”

In some embodiments, the salt of Compound 1 is a camphorsulfonic acidsalt. The camphorsulfonic acid salt can be represented by its chemicalname:3-(cyanomethyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamidecamsylate; or3-(cyanomethyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamidemono-camphorsulfonic acid salt. The camphorsulfonic acid salt ofCompound 1 is referred to herein as “Compound 1 camsylate.”

In some embodiments, the salt of Compound 1 is an isethionic acid salt.The isethionic acid salt can be represented by its chemical name:3-(cyanomethyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamideisethionate; or3-(cyanomethyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamidemono-isethionic acid salt. The isethionic acid salt of Compound 1 isreferred to herein as “Compound 1 isethionate.”

In some embodiments, the salt of Compound 1 is a 1,2-ethanedisulfonicacid salt. The 1,2-ethanedisulfonic acid salt can be represented by itschemical name:3-(cyanomethyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamideethanedisulfonate; or3-(cyanomethyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamidemono-1,2-ethanedisulfonic acid salt. The 1,2-ethanedisulfonic acid saltof Compound 1 is referred to herein as “Compound 11,2-ethanedisulfonate.”

In some embodiments, the salt of Compound 1 is a sulfuric acid salt. Thesulfuric acid salt can be represented by its chemical name:3-(cyanomethyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamidesulfate. The sulfuric acid salt of Compound 1 is referred to herein as“Compound 1 sulfate.”

Compound 1 and its salts can be isolated as one or more solid forms. Thesolid forms (e.g., crystalline forms) described herein can have certainadvantages, for example, they may have desirable properties, such asease of handling, ease of processing, storage stability, and ease ofpurification. Moreover, the crystalline forms can be useful forimproving the performance characteristics of a pharmaceutical productsuch as dissolution profile, shelf-life and bioavailability.

As used herein, the phrase “solid form” refers to a salt of theinvention in either an amorphous state or a crystalline state(“crystalline form” or “crystalline solid”), whereby a salt of theinvention in a crystalline state may optionally include solvent or waterwithin the crystalline lattice, for example, to form a solvated orhydrated crystalline form. In some embodiments, the salt of the presentinvention is in a crystalline state as described herein. The term“hydrated,” as used herein, is meant to refer to a crystalline form thatincludes one or more water molecules in the crystalline lattice. Example“hydrated” crystalline forms include hemihydrates, monohydrates,dihydrates, and the like. Other hydrated forms such as channel hydratesand the like are also included within the meaning of the term.

In some embodiments, salts of the invention can be prepared by anysuitable method for the preparation of acid addition salts. For example,the free base Compound 1 can be combined with the desired acid in asolvent or in a melt. Alternatively, an acid addition salt of Compound 1can be converted to a different acid addition salt by anion exchange.Salts of the invention which are prepared in a solvent system can beisolated by precipitation from the solvent. Precipitation and/orcrystallization can be induced, for example, by evaporation, reductionof temperature, addition of anti-solvent, or combinations thereof.

In some embodiments, the salts of the invention are crystalline,including crystalline forms which are anhydrous, hydrated, non-solvated,or solvated. Example hydrates include hemihydrates, monohydrates,dihydrates, and the like. In some embodiments, the crystalline salts areanhydrous and non-solvated. By “anhydrous” is meant that the crystallinesalt contains no bound water in the crystal lattice structure, i.e., thecompound does not form a crystalline hydrate.

In some embodiments, the salts of the invention are substantiallyisolated. By “substantially isolated” is meant that the salt is at leastpartially or substantially separated from the environment in which itwas formed or detected. Partial separation can include, for example, acomposition enriched in the salt of the invention. Substantialseparation can include compositions containing at least about 50%, atleast about 60%, at least about 70%, at least about 80%, at least about90%, at least about 95%, at least about 97%, or at least about 99% byweight of the salt.

Salts of the invention also include all isotopes of atoms occurring inthe salts. Isotopes include those atoms having the same atomic numberbut different mass numbers. For example, isotopes of hydrogen includetritium and deuterium.

The salt forms of the invention were found to be highly crystalline, adesirable property which can facilitate, for example, purification ofthe drug such as by crystallization and recrystallization as necessary.Further, a crystalline form tends to be more stable and can be easier tomill or micronize when formulating a drug. Crystalline salts also tendhave excellent properties with respect to solubility and can be moresuitable to be manufactured reproducibly in a clear acid/base ratio,facilitating the preparation of liquid formulations for oral as well asfor intravenous applications.

As used herein, the term “crystalline” or “crystalline form” refers to acrystalline solid form of a chemical compound, including, but notlimited to, a single-component or multiple-component crystal form, e.g.,including solvates, hydrates, clathrates, and a co-crystals. As usedherein, “crystalline form” is meant to refer to a certain latticeconfiguration of a crystalline substance. Different crystalline forms ofthe same substance typically have different crystalline lattices (e.g.,unit cells) which are attributed to different physical properties thatare characteristic of each of the crystalline forms. In some instances,different lattice configurations have different water or solventcontent. The different crystalline lattices can be identified by solidstate characterization methods such as by X-ray powder diffraction(XRPD). Other characterization methods such as differential scanningcalorimetry (DSC), thermogravimetric analysis (TGA), dynamic vaporsorption (DVS), solid state NMR, and the like further help identify thecrystalline form as well as help determine stability and solvent/watercontent.

Crystalline forms of a substance include both solvated (e.g., hydrated)and non-solvated (e.g., anhydrous) forms. A hydrated form is acrystalline form that includes water in the crystalline lattice.Hydrated forms can be stoichiometric hydrates, where the water ispresent in the lattice in a certain water/molecule ratio such as forhemihydrates, monohydrates, dihydrates, etc. Hydrated forms can also benon-stoichiometric, where the water content is variable and dependent onexternal conditions such as humidity.

As used herein, the term “substantially crystalline,” means a majorityof the weight of a sample or preparation of a salt (or hydrate orsolvate thereof) of the invention is crystalline and the remainder ofthe sample is a non-crystalline form (e.g., amorphous form) of the samecompound. In some embodiments, a substantially crystalline sample has atleast about 95% crystallinity (e.g., about 5% of the non-crystallineform of the same compound), preferably at least about 96% crystallinity(e.g., about 4% of the non-crystalline form of the same compound), morepreferably at least about 97% crystallinity (e.g., about 3% of thenon-crystalline form of the same compound), even more preferably atleast about 98% crystallinity (e.g., about 2% of the non-crystallineform of the same compound), still more preferably at least about 99%crystallinity (e.g., about 1% of the non-crystalline form of the samecompound), and most preferably about 100% crystallinity (e.g., about 0%of the non-crystalline form of the same compound). In some embodiments,the term “fully crystalline” means at least about 99% or about 100%crystallinity.

Crystalline forms are most commonly characterized by XRPD. An XRPDpattern of reflections (peaks) is typically considered a fingerprint ofa particular crystalline form. It is well known that the relativeintensities of the XRPD peaks can widely vary depending on, inter alia,the sample preparation technique, crystal size distribution, filters,the sample mounting procedure, and the particular instrument employed.In some instances, new peaks may be observed or existing peaks maydisappear, depending on the type of instrument or the settings (forexample, whether a Ni filter is used or not). As used herein, the term“peak” refers to a reflection having a relative height/intensity of atleast about 4% of the maximum peak height/intensity. Moreover,instrument variation and other factors can affect the 2-theta values.Thus, peak assignments, such as those reported herein, can vary by plusor minus about 0.2° (2-theta), and the term “substantially” as used inthe context of XRPD herein is meant to encompass the above-mentionedvariations.

In the same way, temperature readings in connection with DSC, TGA, orother thermal experiments can vary about ±3° C. depending on theinstrument, particular settings, sample preparation, etc. For example,with DSC it is known that the temperatures observed will depend on therate of the temperature change as well as the sample preparationtechnique and the particular instrument employed. Thus, the valuesreported herein related to DSC thermograms can vary, as indicated above,by ±3° C. Accordingly, a crystalline form reported herein having a DSCthermogram “substantially” as shown in any of the Figures is understoodto accommodate such variation.

The salts and compounds disclosed herein can include all isotopes ofatoms occurring within them. Isotopes include those atoms having thesame atomic number but different mass numbers. For example, isotopes ofhydrogen include tritium and deuterium. Salts and compounds of theinvention can also include all isotopes of atoms occurring in theintermediates or final compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. For example, isotopesof hydrogen include tritium and deuterium. One or more constituent atomsof the compounds of the invention can be replaced or substituted withisotopes of the atoms in natural or non-natural abundance. In someembodiments, the compound includes at least one deuterium atom. Forexample, one or more hydrogen atoms in a compound of the presentdisclosure can be replaced or substituted by deuterium. In someembodiments, the compound includes two or more deuterium atoms. In someembodiments, the compound includes 1, 2, 3, 4, 5, 6, 7 or 8 deuteriumatoms. Synthetic methods for including isotopes into organic compoundsare known in the art.

As used herein, and unless otherwise specified, the term “about”, whenused in connection with a numeric value or range of values which isprovided to describe a particular solid form (e.g., a specifictemperature or temperature range, such as describing a melting,dehydration, or glass transition; a mass change, such as a mass changeas a function of temperature or humidity; a solvent or water content, interms of, for example, mass or a percentage; or a peak position, such asin analysis by, for example, ¹³C NMR, DSC, TGA and XRPD), indicate thatthe value or range of values may deviate to an extent deemed reasonableto one of ordinary skill in the art while still describing theparticular solid form. Specifically, the term “about”, when used in thiscontext, indicates that the numeric value or range of values may vary by5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2% or0.1% of the recited value or range of values while still describing theparticular solid form. When used with respect to XRPD values, the term“about” means that the peak assignments can vary by ±0.2° (2-theta).When used in reference to DSC thermogram values, the term “about” meansthat the temperature assignments can vary by ±3° C.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, the term “melting point” refers to an endothermic eventor endothermal event observed in e.g., a DSC experiment. An endothermicevent is a process or reaction in which a sample absorbs energy from itssurrounding in the form of e.g., heat as in a DSC experiment. Anexothermic event is a process or reaction in which a sample releasesenergy. The process of heat absorption and release can be detected byDSC. In some embodiments, the term “melting point” is used to describethe major endothermic event revealed on a particular DSC thermogram.

The term “room temperature” as used herein, is understood in the art,and refers generally to a temperature, e.g., a reaction temperature,that is about the temperature of the room in which the reaction iscarried out, for example, a temperature from about 20° C. to about 30°C. The term “elevated temperature” as used herein, is understood in theart, and refer generally to a temperature, e.g., a reaction temperature,that is above room temperature, e.g., above 30° C.

Compound 1 Di-HCl Form I

Provided herein is a solid form of Compound 1 di-HCl which iscrystalline, referred to as Form I, which is described below in theExamples. In some embodiments, Form I has a molar ratio of Compound 1 toHCl that is about 1:2.

In some embodiments, Form I has an X-ray diffraction pattern comprisingat least one characteristic peak in degrees 2θ selected from about 5.9°,about 7.1°, and about 9.9°. In some embodiments, Form I has an X-raydiffraction pattern comprising a characteristic peak in degrees 2θ atabout 5.9°. In some embodiments, Form I has an X-ray diffraction patterncomprising a characteristic peak in degrees 2θ at about 7.1°. In someembodiments, Form I has an X-ray diffraction pattern comprising acharacteristic peak in degrees 2θ at about 9.9°.

In some embodiments, Form I has an X-ray diffraction pattern comprisingat least two characteristic peak in degrees 2θ selected from about 5.9°,about 7.1°, and about 9.9°.

In some embodiments, Form I has an X-ray diffraction pattern comprisingcharacteristic peaks in degrees 2θ at about 5.9°, about 7.1°, and about9.9°.

In some embodiments, Form I has an X-ray diffraction pattern comprisingat least four characteristic peaks in degrees 2θ selected from about5.9°, about 7.1°, about 9.9°, about 13.2°, about 15.1°, and about 18.2°.In some embodiments, Form I has an X-ray diffraction pattern comprisingat least three characteristic peaks in degrees 2θ selected from about5.9°, about 7.1°, about 9.9°, about 13.2°, about 15.1°, and about 18.2°.In some embodiments, Form I has an X-ray diffraction pattern comprisingat least two characteristic peaks in degrees 2θ selected from about5.9°, about 7.1°, about 9.9°, about 13.2°, about 15.1°, and about 18.2°.In some embodiments, Form I has an X-ray diffraction pattern comprisingat least one characteristic peaks in degrees 2θ selected from about5.9°, about 7.1°, about 9.9°, about 13.2°, about 15.1°, and about 18.2°.

In some embodiments, Form I has an X-ray diffraction pattern comprisingat least four characteristic peaks in degrees 2θ selected from about3.8°, about 5.9°, about 7.1°, about 9.9°, about 13.2°, about 15.1°,about 16.9°, about 18.2°, about 23.5°, and about 26.1°. In someembodiments, Form I has an X-ray diffraction pattern comprising at leastthree characteristic peaks in degrees 2θ selected from about 3.8°, about5.9°, about 7.1°, about 9.9°, about 13.2°, about 15.1°, about 16.9°,about 18.2°, about 23.5°, and about 26.1°. In some embodiments, Form Ihas an X-ray diffraction pattern comprising at least two characteristicpeaks in degrees 2θ selected from about 3.8°, about 5.9°, about 7.1°,about 9.9°, about 13.2°, about 15.1°, about 16.9°, about 18.2°, about23.5°, and about 26.1°. In some embodiments, Form I has an X-raydiffraction pattern comprising at least one characteristic peaks indegrees 2θ selected from about 3.8°, about 5.9°, about 7.1°, about 9.9°,about 13.2°, about 15.1°, about 16.9°, about 18.2°, about 23.5°, andabout 26.1°.

In some embodiments, Form I has an XRPD pattern with characteristicpeaks as substantially shown in FIG. 1.

In some embodiments, Form I has a DSC thermogram characterized byendotherm peaks at temperatures of about 80° C. and about 175° C. Insome embodiments, Form I has a DSC thermogram characterized by anexotherm peak at a temperature of about 197° C. In some embodiments,Form I has a DSC thermogram characterized by an endotherm peak at atemperature of about 80° C. In some embodiments, Form I has a DSCthermogram characterized by an endotherm peak at a temperature of about175° C. In some embodiments, Form I has a DSC thermogram substantiallyas shown in FIG. 2. In some embodiments, Form I has a TGA thermogramsubstantially as shown in FIG. 3.

In some embodiments, Form I has an X-ray diffraction pattern comprisingat least four characteristic peaks in degrees 2θ selected from about5.9°, about 7.1°, about 9.9°, about 13.2°, about 15.1°, and about 18.2°;and Form I has a DSC thermogram characterized by endotherm peaks attemperatures of about 80° C. and 175° C. In some embodiments, Form I hasan X-ray diffraction pattern comprising at least four characteristicpeaks in degrees 2θ selected from about 5.9°, about 7.1°, about 9.9°,about 13.2°, about 15.1°, and about 18.2°; and Form I has a DSCthermogram characterized by an endotherm peak at a temperature of about80° C. In some embodiments, Form I has an X-ray diffraction patterncomprising at least four characteristic peaks in degrees 2θ selectedfrom about 5.9°, about 7.1°, about 9.9°, about 13.2°, about 15.1°, andabout 18.2°; and Form I has a DSC thermogram characterized by anendotherm peak at a temperature of about 175° C.

Provided herein are also processes for preparing Form I of Compound 1comprising precipitating Compound 1 di-HCl from a solvent. In someembodiments, the solvent is a mixture of a polar and a hydrocarbonsolvent. In some embodiments, the solvent is a mixture of methanol and2-methoxy-2-methylpropane. In some embodiments, the precipitatingcomprises a) heating a solution of Compound 1 di-HCl in methanol to anelevated temperature, b) cooling to a reduced temperature, and c) adding2-methoxy-2-methylpropane. In some embodiments, the elevated temperatureis at least about 50° C., at least about 55° C., at least about 60° C.,or at least about 65° C. In some embodiments, the reduced temperature isambient temperature. In some embodiments, the reduced temperature isabout 23° C.

In some embodiments, Form I can be isolated with a purity of at leastabout 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about98%, or about 99%. In some embodiments, Form I can be isolated with apurity greater than about 99%.

Compound 1 Di-HCl Form H

Provided herein is a solid form of Compound 1 di-HCl, which iscrystalline, referred to as Form II, which is described below in theExamples. In some embodiments, Form II has a molar ratio of Compound 1to HCl that is about 1:2.

In some embodiments, Form II has an X-ray diffraction pattern comprisingat least one characteristic peak in degrees 2θ selected from about 5.8°,about 13.2°, and about 15.1°. In some embodiments, Form II has an X-raydiffraction pattern comprising a characteristic peak in degrees 2θ atabout 5.8°. In some embodiments, Form II has an X-ray diffractionpattern comprising a characteristic peak in degrees 2θ at about 13.2°.In some embodiments, Form II has an X-ray diffraction pattern comprisinga characteristic peak in degrees 2θ at about 15.1°.

In some embodiments, Form II has an X-ray diffraction pattern comprisingat least two characteristic peaks in degrees 2θ selected from about5.8°, about 13.2°, and about 15.1°.

In some embodiments, Form II has an X-ray diffraction pattern comprisingcharacteristic peaks in degrees 2θ selected from about 5.8°, about13.2°, and about 15.1°.

In some embodiments, Form II has an X-ray diffraction pattern comprisingat least four characteristic peaks in degrees 2θ selected from about5.8°, about 13.2°, about 15.1°, about 17.1°, about 20.1° and about20.8°. In some embodiments, Form II has an X-ray diffraction patterncomprising at least three characteristic peaks in degrees 2θ selectedfrom about 5.8°, about 13.2°, about 15.1°, about 17.1°, about 20.1° andabout 20.8°. In some embodiments, Form II has an X-ray diffractionpattern comprising at least two characteristic peaks in degrees 2θselected from about 5.8°, about 13.2°, about 15.1°, about 17.1°, about20.1° and about 20.8°. In some embodiments, Form II has an X-raydiffraction pattern comprising at least one characteristic peak indegrees 2θ selected from about 5.8°, about 13.2°, about 15.1°, about17.1°, about 20.1° and about 20.8°.

In some embodiments, Form II has an X-ray diffraction pattern comprisingat least four characteristic peaks in degrees 2θ selected from about5.8°, about 13.2°, about 15.1°, about 17.1°, about 20.1° about 20.8°,about 22.5°, about 25.4°, about 28.0°, and about 29.1°. In someembodiments, Form II has an X-ray diffraction pattern comprising atleast three characteristic peaks in degrees 2θ selected from about 5.8°,about 13.2°, about 15.1°, about 17.1°, about 20.1° about 20.8°, about22.5°, about 25.4°, about 28.0°, and about 29.1°. In some embodiments,Form II has an X-ray diffraction pattern comprising at least twocharacteristic peaks in degrees 2θ selected from about 5.8°, about13.2°, about 15.1°, about 17.1°, about 20.1° about 20.8°, about 22.5°,about 25.4°, about 28.0°, and about 29.1°. In some embodiments, Form IIhas an X-ray diffraction pattern comprising at least one characteristicpeak in degrees 2θ selected from about 5.8°, about 13.2°, about 15.1°,about 17.1°, about 20.1° about 20.8°, about 22.5°, about 25.4°, about28.0°, and about 29.1°.

In some embodiments, Form II has an XRPD pattern with characteristicpeaks as substantially shown in FIG. 4.

In some embodiments, Form II has a DSC thermogram characterized by anexotherm peak at a temperature of about 198° C. In some embodiments,Form II has a DSC thermogram substantially as shown in FIG. 5. In someembodiments, Form II has a TGA thermogram substantially as shown in FIG.6.

In some embodiments, Form II has an X-ray diffraction pattern comprisingat least four characteristic peaks in degrees 2θ selected from about5.8°, about 13.2°, about 15.1°, about 17.1°, about 20.1° and about20.8°; and Form II has a DSC thermogram characterized by an exothermpeak at a temperature of about 198° C.

Provided herein are also processes for preparing Form II of Compound 1comprising precipitating Compound 1 di-HCl from a solvent. In someembodiments, the solvent is a mixture of a polar and a hydrocarbonsolvent. In some embodiments, the solvent is a mixture of 2-butanone andheptane. In some embodiments, the precipitating comprises a) heating asolution of Compound 1 in a mixture of 2-butanone and heptane to anelevated temperature for a first period of time and b) cooling to areduced temperature for a second period of time. In some embodiments,the elevated temperature is at least about 40° C., at least about 45°C., at least about 50° C., or at least about 55° C. In certainembodiments, the first period of time is between about 3 and 5 h (e.g.,about 4 h). In some embodiments, the reduced temperature is ambienttemperature. In some embodiments, the reduced temperature is about 23°C. In some embodiments, the second period of time is between 12 and 16hours. In some embodiments, the second period of time is longer than 6,12, or 18 hours.

In some embodiments, Form II can be isolated with a purity of at leastabout 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about98%, or about 99%. In some embodiments, Form II can be isolated with apurity greater than about 99%.

Compound 1 Di-HCl Form HI

Provided herein is a solid form of Compound 1 di-HCl which iscrystalline, referred to as Form III, which is described below in theExamples. In some embodiments, Form III has a molar ratio of Compound 1to HCl that is about 1:2.

In some embodiments, Form III has an X-ray diffraction patterncomprising at least one characteristic peak in degrees 2θ selected fromabout 5.4°, about 16.8°, and about 21.9°. In some embodiments, Form IIIhas an X-ray diffraction pattern comprising a characteristic peak indegrees 2θ at about 5.4°. In some embodiments, Form III has an X-raydiffraction pattern comprising a characteristic peak in degrees 2θ atabout 16.8°. In some embodiments, Form III has an X-ray diffractionpattern comprising a characteristic peak in degrees 2θ at about 21.9°.

In some embodiments, Form III has an X-ray diffraction patterncomprising at least two characteristic peaks in degrees 2θ selected fromabout 5.4°, about 16.8°, and about 21.9°.

In some embodiments, Form III has an X-ray diffraction patterncomprising characteristic peaks in degrees 2θ at about 5.4°, about16.8°, and about 21.9°.

In some embodiments, Form III has an X-ray diffraction patterncomprising at least four characteristic peaks in degrees 2θ selectedfrom about 5.4°, about 16.8°, about 21.9°, about 27.7°, and about 28.6°.In some embodiments, Form III has an X-ray diffraction patterncomprising at least three characteristic peaks in degrees 2θ selectedfrom about 5.4°, about 16.8°, about 21.9°, about 27.7°, and about 28.6°.In some embodiments, Form III has an X-ray diffraction patterncomprising at least two characteristic peaks in degrees 2θ selected fromabout 5.4°, about 16.8°, about 21.9°, about 27.7°, and about 28.6°. Insome embodiments, Form III has an X-ray diffraction pattern comprisingat least one characteristic peak in degrees 2θ selected from about 5.4°,about 16.8°, about 21.9°, about 27.7°, and about 28.6°.

In some embodiments, Form III has an X-ray diffraction patterncomprising at least four characteristic peaks in degrees 2θ selectedfrom about 5.4°, about 6.7°, about 16.4°, about 16.8°, about 18.2°,about 19.5°, about 21.9°, about 22.2°, about 23.3°, about 27.4°, andabout 28.6°. In some embodiments, Form III has an X-ray diffractionpattern comprising at least three characteristic peaks in degrees 2θselected from about 5.4°, about 6.7°, about 16.4°, about 16.8°, about18.2°, about 19.5°, about 21.9°, about 22.2°, about 23.3°, about 27.4°,and about 28.6°. In some embodiments, Form III has an X-ray diffractionpattern comprising at least two characteristic peaks in degrees 2θselected from about 5.4°, about 6.7°, about 16.4°, about 16.8°, about18.2°, about 19.5°, about 21.9°, about 22.2°, about 23.3°, about 27.4°,and about 28.6°. In some embodiments, Form III has an X-ray diffractionpattern comprising at least one characteristic peak in degrees 2θselected from about 5.4°, about 6.7°, about 16.4°, about 16.8°, about18.2°, about 19.5°, about 21.9°, about 22.2°, about 23.3°, about 27.4°,and about 28.6°.

In some embodiments, Form III has an XRPD pattern with characteristicpeaks as substantially shown in FIG. 7.

Provided herein are also processes for preparing Form III comprisingprecipitating Compound 1 di-HCl from a solvent. In some embodiments, thesolvent is a polar solvent. In some embodiments, the solvent is1,4-dioxane. In some embodiments, the precipitating comprises stirring asolution of Compound 1 di-HCl in 1,4-dioxane for a period of time andfiltering the mixture. In some embodiments, the period of time isgreater than 12 h. In some embodiments, the period of time is greaterthan about 1 day. In some embodiments, the period of time is greaterthan about two days. In some embodiments, the period of time is about 2days. In some embodiments, Form III can be isolated with a purity of atleast about 80%, about 85%, about 90%, about 95%, about 96%, about 97%,about 98%, or about 99%. In some embodiments, Form III can be isolatedwith a purity greater than about 99%.

Compound 1 Di-HCl Form IV

Provided herein is a solid form of Compound 1 di-HCl which iscrystalline, referred to as Form IV, which is described below in theExamples. In some embodiments, Form IV has a molar ratio of Compound 1to HCl that is about 1:2.

In some embodiments, Form IV has an X-ray diffraction pattern comprisingat least one characteristic peak in degrees 2θ selected from about 5.8°,about 17.4°, and about 18.3°. In some embodiments, Form IV has an X-raydiffraction pattern comprising a characteristic peak in degrees 2-thetaat about 5.8°. In some embodiments, Form IV has an X-ray diffractionpattern comprising a characteristic peak in degrees 2-theta at about17.4°. In some embodiments, Form IV has an X-ray diffraction patterncomprising a characteristic peak in degrees 2-theta at about 18.3°.

In some embodiments, Form IV has an X-ray diffraction pattern comprisingat least two characteristic peaks in degrees 2θ selected from about5.8°, about 17.4°, and about 18.3°.

In some embodiments, Form IV has an X-ray diffraction pattern comprisingcharacteristic peaks in degrees 2θ selected from about 5.8°, about17.4°, and about 18.3°.

In some embodiments, Form IV has an X-ray diffraction pattern comprisingat least four characteristic peaks in degrees 2θ selected from about5.8°, about 17.4°, about 18.3°, about 20.9°, about 22.5°, and about26.9°. In some embodiments, Form IV has an X-ray diffraction patterncomprising at least three characteristic peaks in degrees 2θ selectedfrom about 5.8°, about 17.4°, about 18.3°, about 20.9°, about 22.5°, andabout 26.9°. In some embodiments, Form IV has an X-ray diffractionpattern comprising at least two characteristic peaks in degrees 2θselected from about 5.8°, about 17.4°, about 18.3°, about 20.9°, about22.5°, and about 26.9°. In some embodiments, Form IV has an X-raydiffraction pattern comprising at least one characteristic peak indegrees 2θ selected from about 5.8°, about 17.4°, about 18.3°, about20.9°, about 22.5°, and about 26.9°.

In some embodiments, Form IV has an X-ray diffraction pattern comprisingat least four characteristic peaks in degrees 2θ selected from about5.8°, about 17.4°, about 18.3°, about 20.9°, about 21.4°, about 22.5°,about 24.2°, about 25.6°, and about 26.9°. In some embodiments, Form IVhas an X-ray diffraction pattern comprising at least threecharacteristic peaks in degrees 2θ selected from about 5.8°, about17.4°, about 18.3°, about 20.9°, about 21.4°, about 22.5°, about 24.2°,about 25.6°, and about 26.9°. In some embodiments, Form IV has an X-raydiffraction pattern comprising at least two characteristic peaks indegrees 2θ selected from about 5.8°, about 17.4°, about 18.3°, about20.9°, about 21.4°, about 22.5°, about 24.2°, about 25.6°, and about26.9°. In some embodiments, Form IV has an X-ray diffraction patterncomprising at least one characteristic peak in degrees 2θ selected fromabout 5.8°, about 17.4°, about 18.3°, about 20.9°, about 21.4°, about22.5°, about 24.2°, about 25.6°, and about 26.9°.

In some embodiments, Form IV has an XRPD pattern with characteristicpeaks as substantially shown in FIG. 8.

Provided herein are also processes for preparing Form IV comprisingprecipitating Compound 1 di-HCl from a solvent. In some embodiments, thesolvent is a non-polar aromatic solvent. In some embodiments, thesolvent is toluene. In some embodiments, the precipitating comprisesstirring a solution of Compound 1 di-HCl in toluene for a period of timeand filtering the mixture. In some embodiments, the period of time isgreater than 12 h. In some embodiments, the period of time is greaterthan about 1 day. In some embodiments, the period of time is greaterthan about two days. In some embodiments, the period of time is about 2days.

In some embodiments, Form IV can be isolated with a purity of at leastabout 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about98%, or about 99%. In some embodiments, Form IV can be isolated with apurity greater than about 99%.

Compound 1 Di-HCl Form V

Provided herein is a solid form of Compound 1 di-HCl which iscrystalline, referred to as Form V, which is described below in theExamples. In some embodiments, Form V has a molar ratio of Compound 1 toHCl that is about 1:2.

In some embodiments, Form V has an X-ray diffraction pattern comprisingat least one characteristic peak in degrees 2θ selected from about 5.4°,about 6.8°, and about 13.1°. In some embodiments, Form V has an X-raydiffraction pattern comprising a characteristic peak in degrees 2-thetaat about 5.4°. In some embodiments, Form V has an X-ray diffractionpattern comprising a characteristic peak in degrees 2-theta at about6.8°. In some embodiments, Form V has an X-ray diffraction patterncomprising a characteristic peak in degrees 2-theta at about 13.1°.

In some embodiments, Form V has an X-ray diffraction pattern comprisingat least two characteristic peaks in degrees 2θ selected from about5.4°, about 6.8°, and about 13.1°.

In some embodiments, Form V has an X-ray diffraction pattern comprisingcharacteristic peaks in degrees 2θ at about 5.4°, about 6.8°, and about13.1°.

In some embodiments, Form V has an X-ray diffraction pattern comprisingat least four characteristic peaks in degrees 2θ selected from about5.4°, about 6.8°, about 13.1°, about 15.2, and about 21.7°. In someembodiments, Form V has an X-ray diffraction pattern comprising at leastthree characteristic peaks in degrees 2θ selected from about 5.4°, about6.8°, about 13.1°, about 15.2, and about 21.7°. In some embodiments,Form V has an X-ray diffraction pattern comprising at least twocharacteristic peaks in degrees 2θ selected from about 5.4°, about 6.8°,about 13.1°, about 15.2, and about 21.7°. In some embodiments, Form Vhas an X-ray diffraction pattern comprising at least one characteristicpeak in degrees 2θ selected from about 5.4°, about 6.8°, about 13.1°,about 15.2, and about 21.7°.

In some embodiments, Form V has an X-ray diffraction pattern comprisingat least four characteristic peaks in degrees 2θ selected from about4.1°, about 5.4°, about 6.8°, about 13.1°, about 15.2°, about 16.7°,about 17.3°, about 20.5°, about 21.7°, and about 25.6°. In someembodiments, Form V has an X-ray diffraction pattern comprising at leastthree characteristic peaks in degrees 2θ selected from about 4.1°, about5.4°, about 6.8°, about 13.1°, about 15.2°, about 16.7°, about 17.3°,about 20.5°, about 21.7°, and about 25.6°. In some embodiments, Form Vhas an X-ray diffraction pattern comprising at least two characteristicpeaks in degrees 2θ selected from about 4.1°, about 5.4°, about 6.8°,about 13.1°, about 15.2°, about 16.7°, about 17.3°, about 20.5°, about21.7°, and about 25.6°. In some embodiments, Form V has an X-raydiffraction pattern comprising at least one characteristic peak indegrees 2θ selected from about 4.1°, about 5.4°, about 6.8°, about13.1°, about 15.2°, about 16.7°, about 17.3°, about 20.5°, about 21.7°,and about 25.6°.

In some embodiments, Form V has an XRPD pattern with characteristicpeaks as substantially shown in FIG. 9.

In some embodiments, Form V has a DSC thermogram characterized by anexotherm peak at a temperature of about 198° C. In some embodiments,Form V has a DSC thermogram substantially as shown in FIG. 10. In someembodiments, Form V has a TGA thermogram substantially as shown in FIG.11.

In some embodiments, Form V has an X-ray diffraction pattern comprisingat least four characteristic peaks in degrees 2θ selected from about5.4°, about 6.8°, about 13.1°, about 15.2, and about 21.7°; and Form Vhas a DSC thermogram characterized by an exotherm peak at a temperatureof about 198° C.

Provided herein are also processes for preparing Form V comprisingprecipitating Compound 1 di-HCl from a solvent. In some embodiments, thesolvent is an ether. In some embodiments, the solvent is MTBE. In someembodiments, the precipitating comprises stirring a solution of Compound1 di-HCl in MTBE for a period of time and filtering the mixture. In someembodiments, the period of time is greater than 12 h. In someembodiments, the period of time is greater than about 1 day. In someembodiments, the period of time is greater than about two days. In someembodiments, the period of time is about 2 days.

In some embodiments, Form V can be isolated with a purity of at leastabout 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about98%, or about 99%. In some embodiments, Form V can be isolated with apurity greater than about 99%.

Compound 1 Mono-HCl

Provided herein is a solid form of Compound 1 mono-HCl which iscrystalline and is described below in the Examples. In some embodiments,Compound 1 mono-HCl has a molar ratio of Compound 1 to HCl that is about1:1.

Compound 1 mono-HCl can be prepared by any suitable method for thepreparation of HCl acid addition salts. For example, Compound 1 can becombined with HCl (e.g., about 1.0 equiv or more) in a first solvent. Insome embodiments, the first solvent is a mixture of dichloromethane andisopropanol. In certain embodiments, Compound 1 is combined with about 1to about 2 molar equivalents of HCl. In certain embodiments, Compound 1is combined with about 1.0 to about 1.1 molar equivalents of HCl. Incertain embodiments, Compound 1 is combined with about 1.05 molarequivalents of HCl.

Compound 1 mono-HCl can then be isolated by partially evaporating thefirst solvent and then precipitating Compound 1 mono-HCl from a solutioncomprising Compound 1 mono-HCl and a second solvent. In someembodiments, the second solvent is isopropanol. In some embodiments, thesecond solvent is a mixture of isopropanol and dichloromethane. In someembodiments, precipitation is completed within about 2 hours, but longerand shorter periods are possible depending on the choice of solvent andtemperature.

In some embodiments, Compound 1 mono-HCl has an X-ray diffractionpattern comprising at least one characteristic peak in degrees 2θselected from about 10.3°, about 12.8°, and about 15.6°. In someembodiments, Compound 1 mono-HCl has an X-ray diffraction pattern indegrees 2θ comprising a characteristic peak at about 10.3°. In someembodiments, Compound 1 mono-HCl has an X-ray diffraction patterncomprising a characteristic peak in degrees 2θ at about 12.8°. In someembodiments, Compound 1 mono-HCl has an X-ray diffraction patterncomprising a characteristic peak in degrees 2θ at about 15.6°.

In some embodiments, Compound 1 mono-HCl has an X-ray diffractionpattern comprising at least two characteristic peaks in degrees 2θselected from about 10.3°, about 12.8°, and about 15.6°.

In some embodiments, Compound 1 mono-HCl has an X-ray diffractionpattern comprising characteristic peaks in degrees 2θ selected fromabout 10.3°, about 12.8°, and about 15.6°.

In some embodiments, Compound 1 mono-HCl has an X-ray diffractionpattern comprising at least four characteristic peaks in degrees 2θselected from about 10.3°, about 12.8°, about 15.6°, about 16.4°, about21.5°, and about 25.7°. In some embodiments, Compound 1 mono-HCl has anX-ray diffraction pattern comprising at least three characteristic peaksin degrees 2θ selected from about 10.3°, about 12.8°, about 15.6°, about16.4°, about 21.5°, and about 25.7°. In some embodiments, Compound 1mono-HCl has an X-ray diffraction pattern comprising at least twocharacteristic peaks in degrees 2θ selected from about 10.3°, about12.8°, about 15.6°, about 16.4°, about 21.5°, and about 25.7°. In someembodiments, Compound 1 mono-HCl has an X-ray diffraction patterncomprising at least one characteristic peak in degrees 2θ selected fromabout 10.3°, about 12.8°, about 15.6°, about 16.4°, about 21.5°, andabout 25.7°.

In some embodiments, Compound 1 mono-HCl has an X-ray diffractionpattern comprising at least four characteristic peaks in degrees 2θselected from about 10.3°, about 11.4°, about 12.1°, about 12.8°, about14.2°, about 15.6°, about 16.4°, about 18.4°, about 21.5°, about 22.8°,about 23.5°, about 24.2°, and about 27.5°. In some embodiments, Compound1 mono-HCl has an X-ray diffraction pattern comprising at least threecharacteristic peaks in degrees 2θ selected from about 10.3°, about11.4°, about 12.1°, about 12.8°, about 14.2°, about 15.6°, about 16.4°,about 18.4°, about 21.5°, about 22.8°, about 23.5°, about 24.2°, andabout 27.5°. In some embodiments, Compound 1 mono-HCl has an X-raydiffraction pattern comprising at least two characteristic peaks indegrees 2θ selected from about 10.3°, about 11.4°, about 12.1°, about12.8°, about 14.2°, about 15.6°, about 16.4°, about 18.4°, about 21.5°,about 22.8°, about 23.5°, about 24.2°, and about 27.5°. In someembodiments, Compound 1 mono-HCl has an X-ray diffraction patterncomprising at least one characteristic peak in degrees 2θ selected fromabout 10.3°, about 11.4°, about 12.1°, about 12.8°, about 14.2°, about15.6°, about 16.4°, about 18.4°, about 21.5°, about 22.8°, about 23.5°,about 24.2°, and about 27.5°.

In some embodiments, Compound 1 mono-HCl has an XRPD pattern withcharacteristic peaks as substantially shown in FIG. 18.

In some embodiments, Compound 1 mono-HCl has a DSC thermogramcharacterized by an exotherm peak at a temperature of about 178° C. andan endotherm peak at a temperature of about 204° C. In some embodiments,Compound 1 mono-HCl has a DSC thermogram characterized by an exothermpeak at a temperature of about 178° C. In some embodiments, Compound 1mono-HCl has a DSC thermogram characterized by an endotherm peak at atemperature of about 200° C. In some embodiments, Compound 1 mono-HClhas a DSC thermogram substantially as shown in FIG. 19. In someembodiments, Compound 1 mono-HCl has a TGA thermogram substantially asshown in FIG. 20.

In some embodiments, Compound 1 mono-HCl has an X-ray diffractionpattern comprising at least four characteristic peaks in degrees 2θselected from about 10.3°, about 12.8°, about 15.6°, about 16.4°, about21.5°, and about 25.7°; and Compound 1 mono-HCl has a DSC thermogramcharacterized by an exotherm peak at a temperature of about 178° C. Insome embodiments, Compound 1 mono-HCl has an X-ray diffraction patterncomprising at least four characteristic peaks in degrees 2θ selectedfrom about 10.3°, about 12.8°, about 15.6°, about 16.4°, about 21.5°,and about 25.7°; and Compound 1 mono-HCl has a DSC thermogramcharacterized by an endotherm peak at a temperature of about 204° C.

In some embodiments, Compound 1 mono-HCl can be isolated with a purityof at least about 80%, about 85%, about 90%, about 95%, about 96%, about97%, about 98%, or about 99%. In some embodiments, Compound 1 mono-HClcan be isolated with a purity greater than about 99%.

Compound 1 Di-Mesylate

Provided herein is a solid form of Compound 1 di-mesylate, which iscrystalline and is described below in the Examples. In some embodiments,Compound 1 di-mesylate has a molar ratio of Compound 1 tomethanesulfonic acid that is about 1:2.

Compound 1 di-mesylate can be prepared by any suitable method for thepreparation of methanesulfonic acid addition salts. For example,Compound 1 can be combined with methanesulfonic acid (e.g., about 2equiv or more) in a first solvent. In certain embodiments, Compound 1 iscombined with about 2 to about 5 molar equivalents of methanesulfonicacid. In certain embodiments, Compound 1 is combined with about 2 toabout 3 molar equivalents of methanesulfonic acid. In certainembodiments, Compound 1 is combined with about 2.5 molar equivalents ofmethanesulfonic acid. In some embodiments, the first solvent is amixture of alcohols and dichloromethane. In some embodiments, the firstsolvent is a mixture of methanol and dichloromethane. In someembodiments, the first solvent is a mixture of methanol, isopropanol,and dichloromethane.

Compound 1 di-mesylate can then be isolated by partially evaporating thefirst solvent and then precipitating Compound 1 di-mesylate from asolution comprising Compound 1 di-mesylate and a second solvent. In someembodiments, the second solvent is methanol. In some embodiments, thesecond solvent is isopropanol. In some embodiments, the second solventis a mixture of isopropanol and methanol. In some embodiments, thesecond solvent is a mixture of isopropanol, methanol, anddichloromethane. In some embodiments, precipitation is completed withinabout 2 hours, but longer and shorter periods are possible depending onthe choice of solvent and temperature.

In some embodiments, Compound 1 di-mesylate has an X-ray diffractionpattern comprising at least one characteristic peak in degrees 2θselected from about 3.9°, about 5.8°, and about 11.8°. In someembodiments, Compound 1 di-mesylate has an X-ray diffraction patterncomprising a characteristic peak in degrees 2θ at about 3.9°. In someembodiments, Compound 1 di-mesylate has an X-ray diffraction patterncomprising a characteristic peak in degrees 2θ at about 5.8°. In someembodiments, Compound 1 di-mesylate has an X-ray diffraction patterncomprising a characteristic peak in degrees 2θ at about 11.8°.

In some embodiments, Compound 1 di-mesylate has an X-ray diffractionpattern comprising at least two characteristic peaks in degrees 2θselected from about 3.9°, about 5.8°, and about 11.8°.

In some embodiments, Compound 1 di-mesylate has an X-ray diffractionpattern comprising characteristic peaks in degrees 2θ selected fromabout 3.9°, about 5.8°, and about 11.8°.

In some embodiments, Compound 1 di-mesylate has an X-ray diffractionpattern comprising at least four characteristic peaks in degrees 2θselected from about 3.9°, about 5.8°, about 11.8°, about 14.3°, about15.8° and about 19.1°. In some embodiments, Compound 1 di-mesylate hasan X-ray diffraction pattern comprising at least three characteristicpeaks in degrees 2θ selected from about 3.9°, about 5.8°, about 11.8°,about 14.3°, about 15.8° and about 19.1°. In some embodiments, Compound1 di-mesylate has an X-ray diffraction pattern comprising at least twocharacteristic peaks in degrees 2θ selected from about 3.9°, about 5.8°,about 11.8°, about 14.3°, about 15.8° and about 19.1°. In someembodiments, Compound 1 di-mesylate has an X-ray diffraction patterncomprising at least one characteristic peak in degrees 2θ selected fromabout 3.9°, about 5.8°, about 11.8°, about 14.3°, about 15.8° and about19.1°.

In some embodiments, Compound 1 di-mesylate has an X-ray diffractionpattern comprising at least four characteristic peaks in degrees 2θselected from about 3.9°, about 5.8°, about 11.8°, about 14.3°, about15.8°, about 19.1°, about 20.2°, about 21.9°, about 22.8°, about 25.2°,and about 25.9°. In some embodiments, Compound 1 di-mesylate has anX-ray diffraction pattern comprising at least three characteristic peaksin degrees 2θ selected from about 3.9°, about 5.8°, about 11.8°, about14.3°, about 15.8°, about 19.1°, about 20.2°, about 21.9°, about 22.8°,about 25.2°, and about 25.9°. In some embodiments, Compound 1di-mesylate has an X-ray diffraction pattern comprising at least twocharacteristic peaks in degrees 2θ selected from about 3.9°, about 5.8°,about 11.8°, about 14.3°, about 15.8°, about 19.1°, about 20.2°, about21.9°, about 22.8°, about 25.2°, and about 25.9°. In some embodiments,Compound 1 di-mesylate has an X-ray diffraction pattern comprising atleast one characteristic peak in degrees 2θ selected from about 3.9°,about 5.8°, about 11.8°, about 14.3°, about 15.8°, about 19.1°, about20.2°, about 21.9°, about 22.8°, about 25.2°, and about 25.9°.

In some embodiments, Compound 1 di-mesylate has an XRPD pattern withcharacteristic peaks as substantially shown in FIG. 12.

In some embodiments, Compound 1 di-mesylate has a DSC thermogramcharacterized by an exotherm peak at a temperature of about 201° C. Insome embodiments, Compound 1 di-mesylate has a DSC thermogramsubstantially as shown in FIG. 13. In some embodiments, Compound 1di-mesylate has a TGA thermogram substantially as shown in FIG. 14.

In some embodiments, Compound 1 di-mesylate has an X-ray diffractionpattern comprising at least four characteristic peaks in degrees 2θselected from about 3.9°, about 5.8°, about 11.8°, about 14.3°, about15.8° and about 19.1°; and Compound 1 di-mesylate has a DSC thermogramcharacterized by an exotherm peak at a temperature of about 201° C.

In some embodiments, Compound 1 di-mesylate can be isolated with apurity of at least about 80%, about 85%, about 90%, about 95%, about96%, about 97%, about 98%, or about 99%. In some embodiments, Compound 1di-mesylate can be isolated with a purity greater than about 99%.

Compound 1 Mono-Mesylate

Provided herein is a solid form of Compound 1 mono-mesylate, which iscrystalline and is described below in the Examples. In some embodiments,Compound 1 mono-mesylate has a molar ratio of Compound 1 tomethanesulfonic acid that is about 1:1.

Compound 1 mono-mesylate can be prepared by any suitable method for thepreparation of methanesulfonic acid addition salts. For example,Compound 1 can be combined with methanesulfonic acid (e.g., about 1.0equiv or more) in a solvent and the resulting salt can be isolated byfiltering the salt from solution. In some embodiments, the resultingsalt is isolated as crystalline Compound 1 mono-mesylate. In certainembodiments, Compound 1 is combined with about 1 to about 3 molarequivalents of methanesulfonic acid. In some embodiments, Compound 1 iscombined with about 1 to about 2 molar equivalents of methanesulfonicacid. In certain embodiments, Compound 1 is combined with about 1.5 toabout 2.5 molar equivalents of methanesulfonic acid. In certainembodiments, Compound 1 is combined with about 2.1 molar equivalents ofmethanesulfonic acid. In some embodiments, the solvent containsdichloromethane, methanol, ethanol, 1-propanol, or isopropanol. In someembodiments, the solvent is methanol. In some embodiments, the solventis isopropanol. In some embodiments, the solvent is a mixture ofmethanol, isopropanol, and dichloromethane.

In some embodiments, Compound 1 mono-mesylate has an X-ray diffractionpattern comprising at least one characteristic peak in degrees 2θselected from about 4.7°, about 9.5°, and about 14.5°. In someembodiments, Compound 1 mono-mesylate has an X-ray diffraction patterncomprising a characteristic peak in degrees 2θ at about 4.7°. In someembodiments, Compound 1 mono-mesylate has an X-ray diffraction patterncomprising a characteristic peak in degrees 2θ at about 9.5°. In someembodiments, Compound 1 mono-mesylate has an X-ray diffraction patterncomprising a characteristic peak in degrees 2θ at about 14.5°.

In some embodiments, Compound 1 mono-mesylate has an X-ray diffractionpattern comprising at least two characteristic peaks in degrees 2θselected from about 4.7°, about 9.5°, and about 14.5°.

In some embodiments, Compound 1 mono-mesylate has an X-ray diffractionpattern comprising characteristic peaks in degrees 2θ selected fromabout 4.7°, about 9.5°, and about 14.5°.

In some embodiments, Compound 1 mono-mesylate has an X-ray diffractionpattern comprising at least four characteristic peaks in degrees 2θselected from about 4.7°, about 9.5°, about 12.4°, about 14.5°, about15.9°, about 16.6°, about 18.6°, and about 21.8°. In some embodiments,Compound 1 mono-mesylate has an X-ray diffraction pattern comprising atleast three characteristic peaks in degrees 2θ selected from about 4.7°,about 9.5°, about 12.4°, about 14.5°, about 15.9°, about 16.6°, about18.6°, and about 21.8°. In some embodiments, Compound 1 mono-mesylatehas an X-ray diffraction pattern comprising at least two characteristicpeaks in degrees 2θ selected from about 4.7°, about 9.5°, about 12.4°,about 14.5°, about 15.9°, about 16.6°, about 18.6°, and about 21.8°. Insome embodiments, Compound 1 mono-mesylate has an X-ray diffractionpattern comprising at least one characteristic peak in degrees 2θselected from about 4.7°, about 9.5°, about 12.4°, about 14.5°, about15.9°, about 16.6°, about 18.6°, and about 21.8°.

In some embodiments, Compound 1 mono-mesylate has an X-ray diffractionpattern comprising at least four characteristic peaks in degrees 2θselected from about 4.7°, about 9.5°, about 12.4°, about 14.5°, about15.9°, about 16.6°, about 17.8°, about 18.6°, about 19.2°, about 20.8°,about 21.8°, and about 22.6°. In some embodiments, Compound 1mono-mesylate has an X-ray diffraction pattern comprising at least threecharacteristic peaks in degrees 2θ selected from about 4.7°, about 9.5°,about 12.4°, about 14.5°, about 15.9°, about 16.6°, about 17.8°, about18.6°, about 19.2°, about 20.8°, about 21.8°, and about 22.6°. In someembodiments, Compound 1 mono-mesylate has an X-ray diffraction patterncomprising at least two characteristic peaks in degrees 2θ selected fromabout 4.7°, about 9.5°, about 12.4°, about 14.5°, about 15.9°, about16.6°, about 17.8°, about 18.6°, about 19.2°, about 20.8°, about 21.8°,and about 22.6°. In some embodiments, Compound 1 mono-mesylate has anX-ray diffraction pattern comprising at least one characteristic peak indegrees 2θ selected from about 4.7°, about 9.5°, about 12.4°, about14.5°, about 15.9°, about 16.6°, about 17.8°, about 18.6°, about 19.2°,about 20.8°, about 21.8°, and about 22.6°.

In some embodiments, Compound 1 mono-mesylate has an XRPD pattern withcharacteristic peaks as substantially shown in FIG. 35.

In some embodiments, Compound 1 mono-mesylate has a DSC thermogramcharacterized by an endotherm peak at a temperature of about 187° C. Insome embodiments, Compound 1 mono-mesylate has a DSC thermogramsubstantially as shown in FIG. 36.

In some embodiments, Compound 1 mono-mesylate has an X-ray diffractionpattern comprising at least four characteristic peaks in degrees 2θselected from about 4.7°, about 9.5°, about 12.4°, about 14.5°, about15.9°, about 16.6°, about 18.6°, and about 21.8°; and Compound 1mono-mesylate has a DSC thermogram exhibiting an endotherm peak at atemperature of about 187° C.

In some embodiments, Compound 1 mono-mesylate can be isolated with apurity of at least about 80%, about 85%, about 90%, about 95%, about96%, about 97%, about 98%, or about 99%. In some embodiments, Compound 1mono-mesylate can be isolated with a purity greater than about 99%.

Compound 1 Malonate

Provided herein is a solid form of Compound 1 malonate which iscrystalline and is described below in the Examples. In some embodiments,the solid form has a molar ratio of Compound 1 to malonic acid that isabout 1:1.

Compound 1 malonate can be prepared by any suitable method for thepreparation of malonic acid addition salts. For example, Compound 1 canbe combined with malonic acid (e.g., about 1.0 equiv or more) in a firstsolvent. In some embodiments, Compound 1 is combined with about 1 toabout 2 molar equivalents of malonic acid. In certain embodiments,Compound 1 is combined with about 2 to about 3 molar equivalents ofmalonic acid. In certain embodiments, Compound 1 is combined with about2.5 molar equivalents of malonic acid. In some embodiments, the firstsolvent is a mixture of isopropanol and dichloromethane. In someembodiments, the first solvent is isopropanol. In some embodiments, thefirst solvent is dichloromethane.

Compound 1 malonate can then be isolated by partially evaporating thefirst solvent and then precipitating Compound 1 malonate from a solutioncomprising Compound 1 malonate and a second solvent. In someembodiments, the second solvent is isopropanol. In some embodiments, thesecond solvent is a mixture of isopropanol and dichloromethane. In someembodiments, precipitation is completed within about 2 hours, but longerand shorter periods are possible depending on the choice of solvent andtemperature.

In some embodiments, Compound 1 malonate has an X-ray diffractionpattern comprising at least one characteristic peak in degrees 2θselected from about 4.9°, about 13.1°, and about 14.8°. In someembodiments, Compound 1 malonate has an X-ray diffraction patterncomprising a characteristic peak in degrees 2θ at about 4.9°. In someembodiments, Compound 1 malonate has an X-ray diffraction patterncomprising a characteristic peak in degrees 2θ at about 13.1°. In someembodiments, Compound 1 malonate has an X-ray diffraction patterncomprising a characteristic peak in degrees 2θ at about 14.8°.

In some embodiments, Compound 1 malonate has an X-ray diffractionpattern comprising at least two characteristic peaks in degrees 2θselected from about 4.9°, about 13.1°, and about 14.8°.

In some embodiments, Compound 1 malonate has an X-ray diffractionpattern comprising characteristic peaks in degrees 2θ selected fromabout 4.9°, about 13.1°, and about 14.8°.

In some embodiments, Compound 1 malonate has an X-ray diffractionpattern comprising at least four characteristic peaks in degrees 2θselected from about 4.9°, about 13.1°, about 14.8°, about 16.1°, about16.8°, about 17.7°, about 20.0°, and about 22.2°. In some embodiments,Compound 1 malonate has an X-ray diffraction pattern comprising at leastthree characteristic peaks in degrees 2θ selected from about 4.9°, about13.1°, about 14.8°, about 16.1°, about 16.8°, about 17.7°, about 20.0°,and about 22.2°. In some embodiments, Compound 1 malonate has an X-raydiffraction pattern comprising at least two characteristic peaks indegrees 2θ selected from about 4.9°, about 13.1°, about 14.8°, about16.1°, about 16.8°, about 17.7°, about 20.0°, and about 22.2°. In someembodiments, Compound 1 malonate has an X-ray diffraction patterncomprising at least one characteristic peak in degrees 2θ selected fromabout 4.9°, about 13.1°, about 14.8°, about 16.1°, about 16.8°, about17.7°, about 20.0°, and about 22.2°.

In some embodiments, Compound 1 malonate has an X-ray diffractionpattern comprising at least four characteristic peaks in degrees 2θselected from about 4.9°, about 13.1°, about 14.8°, about 15.4°, about16.1°, about 16.8°, about 17.7°, about 18.3°, about 20.0°, about 22.2°,about 24.5°, and about 25.0°. In some embodiments, Compound 1 malonatehas an X-ray diffraction pattern comprising at least threecharacteristic peaks in degrees 2θ selected from about 4.9°, about13.1°, about 14.8°, about 15.4°, about 16.1°, about 16.8°, about 17.7°,about 18.3°, about 20.0°, about 22.2°, about 24.5°, and about 25.0°. Insome embodiments, Compound 1 malonate has an X-ray diffraction patterncomprising at least two characteristic peaks in degrees 2θ selected fromabout 4.9°, about 13.1°, about 14.8°, about 15.4°, about 16.1°, about16.8°, about 17.7°, about 18.3°, about 20.0°, about 22.2°, about 24.5°,and about 25.0°. In some embodiments, Compound 1 malonate has an X-raydiffraction pattern comprising at least one characteristic peak indegrees 2θ selected from about 4.9°, about 13.1°, about 14.8°, about15.4°, about 16.1°, about 16.8°, about 17.7°, about 18.3°, about 20.0°,about 22.2°, about 24.5°, and about 25.0°. In some embodiments, Compound1 malonate has an XRPD pattern with characteristic peaks assubstantially shown in FIG. 15.

In some embodiments, Compound 1 malonate has a DSC thermogramcharacterized by an endotherm peak at a temperature of about 147° C. andan exotherm peak at a temperature of about 149° C. In some embodiments,Compound 1 malonate has a DSC thermogram characterized by an endothermpeak at a temperature of about 147° C. In some embodiments, Compound 1malonate has a DSC thermogram characterized by an exotherm peak at atemperature of about 149° C. In some embodiments, Compound 1 malonatehas a DSC thermogram substantially as shown in FIG. 16. In someembodiments, Compound 1 malonate has a TGA thermogram substantially asshown in FIG. 17.

In some embodiments, Compound 1 malonate has an X-ray diffractionpattern comprising at least four characteristic peaks in degrees 2θselected from about 4.9°, about 13.1°, about 14.8°, about 16.1°, about16.8°, about 17.7°, about 20.0°, and about 22.2°; and Compound 1malonate has a DSC thermogram characterized by an endotherm peak at atemperature of about 147° C. In some embodiments, Compound 1 malonatehas an X-ray diffraction pattern comprising at least four characteristicpeaks in degrees 2θ selected from about 4.9°, about 13.1°, about 14.8°,about 16.1°, about 16.8°, about 17.7°, about 20.0°, and about 22.2°; andCompound 1 malonate has a DSC thermogram characterized by an exothermpeak at a temperature of about 149° C.

In some embodiments, Compound 1 malonate can be isolated with a purityof at least about 80%, about 85%, about 90%, about 95%, about 96%, about97%, about 98%, or about 99%. In some embodiments, Compound 1 malonatecan be isolated with a purity greater than about 99%.

Compound 1 Esylate

Provided herein is a solid form of Compound 1 esylate which iscrystalline and is described below in the Examples. In some embodiments,the solid form has a molar ratio of Compound 1 to ethanesulfonic acidthat is about 1:1.

Compound 1 esylate can be prepared by any suitable method for thepreparation of ethanesulfonic acid addition salts. For example, Compound1 can be combined with ethanesulfonic acid (e.g., about 1.0 equiv ormore) in a solvent and the resulting salt can be isolated by filteringthe salt from solution. In some embodiments, the resulting salt isisolated as crystalline Compound 1 esylate. In certain embodiments,Compound 1 is combined with about 1 to about 2 molar equivalents ofethanesulfonic acid. In certain embodiments, Compound 1 is combined withabout 1.0 to about 1.5 molar equivalents of ethanesulfonic acid. Incertain embodiments, Compound 1 is combined with about 1.35 molarequivalents of ethanesulfonic acid. In some embodiments, the solvent ismethanol. In some embodiments, the solvent is isopropanol. In someembodiments, the solvent is a mixture of methanol and isopropanol. Insome embodiments, the solution is allowed to stir for about three hoursbefore filtering.

In some embodiments, Compound 1 esylate has an X-ray diffraction patterncomprising at least one characteristic peak in degrees 2θ selected fromabout 4.7°, about 9.4°, and about 12.3°. In some embodiments, Compound 1esylate has an X-ray diffraction pattern comprising a characteristicpeak in degrees 2θ at about 4.7°. In some embodiments, Compound 1esylate has an X-ray diffraction pattern comprising a characteristicpeak in degrees 2θ at about 9.4°. In some embodiments, Compound 1esylate has an X-ray diffraction pattern comprising a characteristicpeak in degrees 2θ at about 12.3°.

In some embodiments, Compound 1 esylate has an X-ray diffraction patterncomprising at least two characteristics peak in degrees 2θ selected fromabout 4.7°, about 9.4°, and about 12.3°.

In some embodiments, Compound 1 esylate has an X-ray diffraction patterncomprising characteristic peaks in degrees 2θ at about 4.7°, about 9.4°,and about 12.3°.

In some embodiments, Compound 1 esylate has an X-ray diffraction patterncomprising at least four characteristics peaks in degrees 2θ selectedfrom about 4.7°, about 9.4°, about 12.3°, about 16.1°, about 16.7°,about 18.9°, about 20.5°, and about 21.7°. In some embodiments, Compound1 esylate has an X-ray diffraction pattern comprising at least threecharacteristics peaks in degrees 2θ selected from about 4.7°, about9.4°, about 12.3°, about 16.1°, about 16.7°, about 18.9°, about 20.5°,and about 21.7°. In some embodiments, Compound 1 esylate has an X-raydiffraction pattern comprising at least two characteristics peaks indegrees 2θ selected from about 4.7°, about 9.4°, about 12.3°, about16.1°, about 16.7°, about 18.9°, about 20.5°, and about 21.7°. In someembodiments, Compound 1 esylate has an X-ray diffraction patterncomprising at least one characteristics peak in degrees 2θ selected fromabout 4.7°, about 9.4°, about 12.3°, about 16.1°, about 16.7°, about18.9°, about 20.5°, and about 21.7°.

In some embodiments, Compound 1 esylate has an X-ray diffraction patterncomprising at least four characteristics peaks in degrees 2θ selectedfrom about 4.7°, about 9.4°, about 12.3°, about 14.7°, about 16.1°,about 16.7°, about 18.0°, about 18.9°, about 20.5°, about 21.7°, about22.8°, and about 24.6°. In some embodiments, Compound 1 esylate has anX-ray diffraction pattern comprising at least three characteristicspeaks in degrees 2θ selected from about 4.7°, about 9.4°, about 12.3°,about 14.7°, about 16.1°, about 16.7°, about 18.0°, about 18.9°, about20.5°, about 21.7°, about 22.8°, and about 24.6°. In some embodiments,Compound 1 esylate has an X-ray diffraction pattern comprising at leasttwo characteristics peaks in degrees 2θ selected from about 4.7°, about9.4°, about 12.3°, about 14.7°, about 16.1°, about 16.7°, about 18.0°,about 18.9°, about 20.5°, about 21.7°, about 22.8°, and about 24.6°. Insome embodiments, Compound 1 esylate has an X-ray diffraction patterncomprising at least one characteristics peak in degrees 2θ selected fromabout 4.7°, about 9.4°, about 12.3°, about 14.7°, about 16.1°, about16.7°, about 18.0°, about 18.9°, about 20.5°, about 21.7°, about 22.8°,and about 24.6°.

In some embodiments, Compound 1 esylate has an XRPD pattern withcharacteristic peaks as substantially shown in FIG. 21.

In some embodiments, Compound 1 esylate has a DSC thermogramcharacterized by an endotherm peak at a temperature of about 185° C. andan exotherm peak at a temperature of about 190° C. In some embodiments,Compound 1 esylate has a DSC thermogram characterized by an endothermpeak at a temperature of about 185° C. In some embodiments, Compound 1esylate has a DSC thermogram characterized by an exotherm peak at atemperature of about 190° C. In some embodiments, Compound 1 esylate hasa DSC thermogram substantially as shown in FIG. 22. In some embodiments,Compound 1 esylate has a TGA thermogram substantially as shown in FIG.23.

In some embodiments, Compound 1 esylate has an X-ray diffraction patterncomprising at least four characteristics peaks in degrees 2θ selectedfrom about 4.7°, about 9.4°, about 12.3°, about 16.1°, about 16.7°,about 18.9°, about 20.5°, and about 21.7°; and Compound 1 esylate has aDSC thermogram characterized by an endotherm peak at a temperature ofabout 185° C. In some embodiments, Compound 1 esylate has an X-raydiffraction pattern comprising at least four characteristics peaks indegrees 2θ selected from about 4.7°, about 9.4°, about 12.3°, about16.1°, about 16.7°, about 18.9°, about 20.5°, and about 21.7°; andCompound 1 esylate has a DSC thermogram characterized by an exothermpeak at a temperature of about 190° C.

In some embodiments, Compound 1 esylate can be isolated with a purity ofat least about 80%, about 85%, about 90%, about 95%, about 96%, about97%, about 98%, or about 99%. In some embodiments, Compound 1 esylatecan be isolated with a purity greater than about 99%.

Compound 1 Maleate

Provided herein is a solid form of Compound 1 maleate which iscrystalline and is described below in the Examples. In some embodiments,the solid form has a molar ratio of Compound 1 to maleic acid that isabout 1:1.

Compound 1 maleate can be prepared by any suitable method for thepreparation of maleic acid addition salts. For example, Compound 1 canbe combined with maleic acid (e.g., about 1.0 equiv or more) in a firstsolvent. In certain embodiments, Compound 1 is combined with about 1 toabout 2 molar equivalents of maleic acid. In certain embodiments,Compound 1 is combined with about 1.0 to about 1.5 molar equivalents ofmaleic acid. In certain embodiments, Compound 1 is combined with about1.35 molar equivalents of maleic acid. In some embodiments, the firstsolvent is methanol. In some embodiments, the first solvent isisopropanol. In some embodiments, the first solvent is a mixture ofmethanol and isopropanol.

Compound 1 maleate can then be isolated by partially evaporating thefirst solvent and then precipitating Compound 1 maleate from a solutioncomprising Compound 1 maleate and a second solvent. In some embodiments,the second solvent is isopropanol. In some embodiments, the secondsolvent is a mixture of isopropanol and methanol. In some embodiments,precipitation is completed within about 2 hours, but longer and shorterperiods are possible depending on the choice of solvent and temperature.

In some embodiments, Compound 1 maleate has an X-ray diffraction patterncomprising at least one characteristic peak in degrees 2θ selected fromabout 3.8°, about 11.5°, and about 15.3°. In some embodiments, Compound1 maleate has an X-ray diffraction pattern comprising a characteristicpeak in degrees 2θ at about 3.8°. In some embodiments, Compound 1maleate has an X-ray diffraction pattern comprising a characteristicpeak in degrees 2θ at about 11.5°. In some embodiments, Compound 1maleate has an X-ray diffraction pattern comprising a characteristicpeak in degrees 2θ at about 15.3°.

In some embodiments, Compound 1 maleate has an X-ray diffraction patterncomprising at least two characteristic peaks in degrees 2θ selected fromabout 3.8°, about 11.5°, and about 15.3°.

In some embodiments, Compound 1 maleate has an X-ray diffraction patterncomprising characteristic peaks in degrees 2θ at about 3.8°, about11.5°, and about 15.3°.

In some embodiments, Compound 1 maleate has an X-ray diffraction patterncomprising at least four characteristic peaks in degrees 2θ selectedfrom about 3.8°, about 9.9°, about 11.5°, about 15.3°, about 16.3°,about 18.4°, about 19.0°, about 19.6°, and about 20.7°. In someembodiments, Compound 1 maleate has an X-ray diffraction patterncomprising at least three characteristic peaks in degrees 2θ selectedfrom about 3.8°, about 9.9°, about 11.5°, about 15.3°, about 16.3°,about 18.4°, about 19.0°, about 19.6°, and about 20.7°. In someembodiments, Compound 1 maleate has an X-ray diffraction patterncomprising at least two characteristic peaks in degrees 2θ selected fromabout 3.8°, about 9.9°, about 11.5°, about 15.3°, about 16.3°, about18.4°, about 19.0°, about 19.6°, and about 20.7°. In some embodiments,Compound 1 maleate has an X-ray diffraction pattern comprising at leastone characteristic peak in degrees 2θ selected from about 3.8°, about9.9°, about 11.5°, about 15.3°, about 16.3°, about 18.4°, about 19.0°,about 19.6°, and about 20.7°. In some embodiments, Compound 1 maleatehas an X-ray diffraction pattern comprising at least four characteristicpeaks in degrees 2θ selected from about 3.8°, about 9.9°, about 11.5°,about 15.3°, about 16.3°, about 18.4°, about 19.0°, about 19.6°, about20.7°, about 21.5°, about 22.9°, about 24.7°, and about 25.2°. In someembodiments, Compound 1 maleate has an X-ray diffraction patterncomprising at least three characteristic peaks in degrees 2θ selectedfrom about 3.8°, about 9.9°, about 11.5°, about 15.3°, about 16.3°,about 18.4°, about 19.0°, about 19.6°, about 20.7°, about 21.5°, about22.9°, about 24.7°, and about 25.2°. In some embodiments, Compound 1maleate has an X-ray diffraction pattern comprising at least twocharacteristic peaks in degrees 2θ selected from about 3.8°, about 9.9°,about 11.5°, about 15.3°, about 16.3°, about 18.4°, about 19.0°, about19.6°, about 20.7°, about 21.5°, about 22.9°, about 24.7°, and about25.2°. In some embodiments, Compound 1 maleate has an X-ray diffractionpattern comprising at least one characteristic peak in degrees 2θselected from about 3.8°, about 9.9°, about 11.5°, about 15.3°, about16.3°, about 18.4°, about 19.0°, about 19.6°, about 20.7°, about 21.5°,about 22.9°, about 24.7°, and about 25.2°. In some embodiments, Compound1 maleate has an XRPD pattern with characteristic peaks as substantiallyshown in FIG. 24.

In some embodiments, Compound 1 maleate has a DSC thermogramcharacterized by an endotherm peak at a temperature of about 158° C. Insome embodiments, Compound 1 maleate has a DSC thermogram characterizedby an endotherm peak at a temperature of about 158° C. In someembodiments, Compound 1 maleate has a DSC thermogram substantially asshown in FIG. 25. In some embodiments, Compound 1 maleate has a TGAthermogram substantially as shown in FIG. 26.

In some embodiments, Compound 1 maleate has an X-ray diffraction patterncomprising at least four characteristic peaks in degrees 2θ selectedfrom about 3.8°, about 9.9°, about 11.5°, about 15.3°, about 16.3°,about 18.4°, about 19.0°, about 19.6°, and about 20.7°; and Compound 1maleate has a DSC thermogram characterized by an endotherm peak at atemperature of about 158° C.

In some embodiments, Compound 1 maleate can be isolated with a purity ofat least about 80%, about 85%, about 90%, about 95%, about 96%, about97%, about 98%, or about 99%. In some embodiments, Compound 1 maleatecan be isolated with a purity greater than about 99%.

Compound 1 Camsylate

Provided herein is a solid form of Compound 1 camsylate which iscrystalline and is described below in the Examples. In some embodiments,the solid form has a molar ratio of Compound 1 to camphorsulfonic acidthat is about 1:1.

Compound 1 camsylate can be prepared by any suitable method for thepreparation of camphorsulfonic acid addition salts. For example,Compound 1 can be combined with camphorsulfonic acid (e.g., about 1.0equiv or more) in a solvent and the resulting salt can be isolated byfiltering the salt from solution. In some embodiments, the resultingsalt is isolated as crystalline Compound 1 camsylate. In certainembodiments, Compound 1 is combined with about 1 to about 3 molarequivalents of camphorsulfonic acid. In some embodiments, Compound 1 iscombined with about 1 to about 2 molar equivalents of camphorsulfonicacid. In certain embodiments, Compound 1 is combined with about 1.5 toabout 2.5 molar equivalents of camphorsulfonic acid. In certainembodiments, Compound 1 is combined with about 2 molar equivalents ofcamphorsulfonic acid. In certain embodiments, the solvent is a mixtureof water, methanol, and dichloromethane. In some embodiments, thesolvent is a mixture of methanol and dichloromethane. In someembodiments, the solvent is methanol. In some embodiments, the solventis dichloromethane.

In some embodiments, Compound 1 camsylate has an X-ray diffractionpattern comprising at least one characteristic peak in degrees 2θselected from about 4.0°, about 7.8°, and about 8.5°. In someembodiments, Compound 1 camsylate has an X-ray diffraction patterncomprising a characteristic peak in degrees 2θ at about 4.0°. In someembodiments, Compound 1 camsylate has an X-ray diffraction patterncomprising a characteristic peak in degrees 2θ at about 7.8°. In someembodiments, Compound 1 camsylate has an X-ray diffraction patterncomprising a characteristic peak in degrees 2θ at about 8.5°.

In some embodiments, Compound 1 camsylate has an X-ray diffractionpattern comprising at least two characteristic peaks in degrees 2θselected from about 4.0°, about 7.8°, and about 8.5°.

In some embodiments, Compound 1 camsylate has an X-ray diffractionpattern comprising characteristic peaks in degrees 2θ at about 4.0°,about 7.8°, and about 8.5°.

In some embodiments, Compound 1 camsylate has an X-ray diffractionpattern comprising at least four characteristic peaks in degrees 2θselected from about 4.0°, about 7.8°, about 8.5°, about 11.4°, about12.8°, about 14.2°, about 16.1°, and about 19.5°. In some embodiments,Compound 1 camsylate has an X-ray diffraction pattern comprising atleast three characteristic peaks in degrees 2θ selected from about 4.0°,about 7.8°, about 8.5°, about 11.4°, about 12.8°, about 14.2°, about16.1°, and about 19.5°. In some embodiments, Compound 1 camsylate has anX-ray diffraction pattern comprising at least two characteristic peaksin degrees 2θ selected from about 4.0°, about 7.8°, about 8.5°, about11.4°, about 12.8°, about 14.2°, about 16.1°, and about 19.5°. In someembodiments, Compound 1 camsylate has an X-ray diffraction patterncomprising at least one characteristic peak in degrees 2θ selected fromabout 4.0°, about 7.8°, about 8.5°, about 11.4°, about 12.8°, about14.2°, about 16.1°, and about 19.5°.

In some embodiments, Compound 1 camsylate has an X-ray diffractionpattern comprising at least four characteristic peaks in degrees 2θselected from about 4.0°, about 7.8°, about 8.5°, about 11.4°, about12.8°, about 14.2°, about 16.1°, about 16.7°, about 17.3°, about 19.5°,about 21.2°, and about 22.5°. In some embodiments, Compound 1 camsylatehas an X-ray diffraction pattern comprising at least threecharacteristic peaks in degrees 2θ selected from about 4.0°, about 7.8°,about 8.5°, about 11.4°, about 12.8°, about 14.2°, about 16.1°, about16.7°, about 17.3°, about 19.5°, about 21.2°, and about 22.5°. In someembodiments, Compound 1 camsylate has an X-ray diffraction patterncomprising at least two characteristic peaks in degrees 2θ selected fromabout 4.0°, about 7.8°, about 8.5°, about 11.4°, about 12.8°, about14.2°, about 16.1°, about 16.7°, about 17.3°, about 19.5°, about 21.2°,and about 22.5°. In some embodiments, Compound 1 camsylate has an X-raydiffraction pattern comprising at least one characteristic peak indegrees 2θ selected from about 4.0°, about 7.8°, about 8.5°, about11.4°, about 12.8°, about 14.2°, about 16.1°, about 16.7°, about 17.3°,about 19.5°, about 21.2°, and about 22.5°.

In some embodiments, Compound 1 camsylate has an XRPD pattern withcharacteristic peaks as substantially shown in FIG. 27.

In some embodiments, Compound 1 camsylate has a DSC thermogramcharacterized by an endotherm peak at a temperature of about 168° C. Insome embodiments, Compound 1 camsylate has a DSC thermogramsubstantially as shown in FIG. 28. In some embodiments, Compound 1camsylate has a TGA thermogram substantially as shown in FIG. 29.

In some embodiments, Compound 1 camsylate has an X-ray diffractionpattern comprising at least four characteristic peaks in degrees 2θselected from about 4.0°, about 7.8°, about 8.5°, about 11.4°, about12.8°, about 14.2°, about 16.1°, and about 19.5°; and Compound 1camsylate has a DSC thermogram characterized by an endotherm peak at atemperature of about 168° C.

In some embodiments, Compound 1 camsylate can be isolated with a purityof at least about 80%, about 85%, about 90%, about 95%, about 96%, about97%, about 98%, or about 99%. In some embodiments, Compound 1 camsylatecan be isolated with a purity greater than about 99%.

Compound 1 Isethionate

Provided herein is a solid form of Compound 1 isethionate which iscrystalline and is described below in the Examples. In some embodiments,the solid form has a molar ratio of Compound 1 to isethionic acid thatis about 1:1.

Compound 1 isethionate can be prepared by any suitable method for thepreparation of isethionic acid addition salts. For example, Compound 1can be combined with isethionic acid (e.g., about 1.0 equiv or more) ina solvent and the resulting salt can be isolated by filtering the saltfrom solution. In some embodiments, the resulting salt is isolated ascrystalline Compound 1 isethionate. In certain embodiments, Compound 1is combined with about 1 to about 3 molar equivalents of isethionicacid. In some embodiments, Compound 1 is combined with about 1 to about2 molar equivalents of isethionic acid. In certain embodiments, Compound1 is combined with about 1.5 to about 2.5 molar equivalents ofisethionic acid. In certain embodiments, Compound 1 is combined withabout 2.2 molar equivalents of isethionic acid. In certain embodiments,the solvent is a mixture of dichloromethane and methanol. In certainembodiments, the solvent is dichloromethane. In certain embodiments, thesolvent is methanol.

In some embodiments, Compound 1 isethionate has an X-ray diffractionpattern comprising at least one characteristic peak in degrees 2θselected from about 6.7°, about 14.9°, and about 18.2°. In someembodiments, Compound 1 isethionate has an X-ray diffraction patterncomprising a characteristic peak in degrees 2θ at about 6.7°. In someembodiments, Compound 1 isethionate has an X-ray diffraction patterncomprising a characteristic peak in degrees 2θ at about 14.9°. In someembodiments, Compound 1 isethionate has an X-ray diffraction patterncomprising a characteristic peak in degrees 2θ at about 18.2°.

In some embodiments, Compound 1 isethionate has an X-ray diffractionpattern comprising at least two characteristic peaks in degrees 2θselected from about 6.7°, about 14.9°, and about 18.2°.

In some embodiments, Compound 1 isethionate has an X-ray diffractionpattern comprising characteristics peak in degrees 2θ at about 6.7°,about 14.9°, and about 18.2°.

In some embodiments, Compound 1 isethionate has an X-ray diffractionpattern comprising at least four characteristic peaks in degrees 2θselected from about 6.7°, about 14.9°, about 15.5°, about 16.7°, about17.7°, about 18.2°, and about 19.1°. In some embodiments, Compound 1isethionate has an X-ray diffraction pattern comprising at least threecharacteristic peaks in degrees 2θ selected from about 6.7°, about14.9°, about 15.5°, about 16.7°, about 17.7°, about 18.2°, and about19.1°. In some embodiments, Compound 1 isethionate has an X-raydiffraction pattern comprising at least two characteristic peaks indegrees 2θ selected from about 6.7°, about 14.9°, about 15.5°, about16.7°, about 17.7°, about 18.2°, and about 19.1°. In some embodiments,Compound 1 isethionate has an X-ray diffraction pattern comprising atleast one characteristic peak in degrees 2θ selected from about 6.7°,about 14.9°, about 15.5°, about 16.7°, about 17.7°, about 18.2°, andabout 19.1°.

In some embodiments, Compound 1 isethionate has an X-ray diffractionpattern comprising at least four characteristic peaks in degrees 2θselected from about 6.7°, about 14.9°, about 15.5°, about 16.7°, about17.7°, about 18.2°, about 19.1°, about 19.9°, about 20.8°, about 22.6°,and about 24.8°. In some embodiments, Compound 1 isethionate has anX-ray diffraction pattern comprising at least three characteristic peaksin degrees 2θ selected from about 6.7°, about 14.9°, about 15.5°, about16.7°, about 17.7°, about 18.2°, about 19.1°, about 19.9°, about 20.8°,about 22.6°, and about 24.8°. In some embodiments, Compound 1isethionate has an X-ray diffraction pattern comprising at least twocharacteristic peaks in degrees 2θ selected from about 6.7°, about14.9°, about 15.5°, about 16.7°, about 17.7°, about 18.2°, about 19.1°,about 19.9°, about 20.8°, about 22.6°, and about 24.8°. In someembodiments, Compound 1 isethionate has an X-ray diffraction patterncomprising at least one characteristic peak in degrees 2θ selected fromabout 6.7°, about 14.9°, about 15.5°, about 16.7°, about 17.7°, about18.2°, about 19.1°, about 19.9°, about 20.8°, about 22.6°, and about24.8°. In some embodiments, Compound 1 isethionate has an XRPD patternwith characteristic peaks as substantially shown in FIG. 30.

In some embodiments, Compound 1 isethionate has a DSC thermogramcharacterized by endotherm peaks at a temperature of about 169° C. andan exotherm peak at a temperature of about 212° C. In some embodiments,Compound 1 isethionate has a DSC thermogram characterized by anendotherm peak at a temperature of about 169° C. In some embodiments,Compound 1 isethionate has a DSC thermogram characterized by an exothermpeak at a temperature of about 212° C. In some embodiments, Compound 1isethionate has a DSC thermogram substantially as shown in FIG. 31. Insome embodiments, Compound 1 isethionate has a TGA thermogramsubstantially as shown in FIG. 32.

In some embodiments, Compound 1 isethionate has an X-ray diffractionpattern comprising at least four characteristic peaks in degrees 2θselected from about 6.7°, about 14.9°, about 15.5°, about 16.7°, about17.7°, about 18.2°, and about 19.1°; and Compound 1 isethionate has aDSC thermogram characterized by an endotherm peak at a temperature ofabout 169° C. In some embodiments, Compound 1 isethionate has an X-raydiffraction pattern comprising at least four characteristic peaks indegrees 2θ selected from about 6.7°, about 14.9°, about 15.5°, about16.7°, about 17.7°, about 18.2°, and about 19.1°; and Compound 1isethionate has a DSC thermogram characterized by an exotherm peak at atemperature of about 212° C.

In some embodiments, Compound 1 isethionate can be isolated with apurity of at least about 80%, about 85%, about 90%, about 95%, about96%, about 97%, about 98%, or about 99%. In some embodiments, Compound 1isethionate can be isolated with a purity greater than about 99%.

Compound 1 1,2-Ethanedisulfonate

Provided herein is a solid form of Compound 1 1,2-ethanedisulfonatewhich is crystalline and is described below in the Examples. In someembodiments, the solid form has a molar ratio of Compound 1 to1,2-ethanedisulfonic acid that is about 1:1.

Compound 1 1,2-ethanedisulfonate can be prepared by any suitable methodfor the preparation of 1,2-ethanedisulfonic acid addition salts. Forexample, Compound 1 can be combined with 1,2-ethanedisulfonic acid(e.g., about 1.0 equiv or more) in a solvent and the resulting salt canbe isolated by filtering the salt from solution. In some embodiments,the resulting salt is isolated as crystalline Compound 11,2-ethanedisulfonate. In certain embodiments, Compound 1 is combinedwith about 1 to about 3 molar equivalents of 1,2-ethanedisulfonic acid.In some embodiments, Compound 1 is combined with about 1 to about 2molar equivalents of 1,2-ethanedisulfonic acid. In certain embodiments,Compound 1 is combined with about 1.5 to about 2.5 molar equivalents of1,2-ethanedisulfonic acid. In certain embodiments, Compound 1 iscombined with about 2.1 molar equivalents of 1,2-ethanedisulfonic acid.In certain embodiments, the solvent is a mixture of isopropanol,methanol, and dichloromethane. In certain embodiments, the solvent is amixture of methanol and dichloromethane. In some embodiments, thesolvent is a mixture of isopropanol and dichloromethane. In someembodiments, the solvent is methanol. In some embodiments, the solventis isopropanol. In some embodiments, the solvent is dichloromethane.

In some embodiments, Compound 1 1,2-ethanedisulfonate has an X-raydiffraction pattern comprising at least one characteristic peak indegrees 2θ selected from about 7.9°, about 10.5°, and about 12.9°. Insome embodiments, Compound 1 1,2-ethanedisulfonate has an X-raydiffraction pattern comprising a characteristic peak in degrees 2θ atabout 7.9°. In some embodiments, Compound 1 1,2-ethanedisulfonate has anX-ray diffraction pattern comprising a characteristic peak in degrees 2θat about 10.5°. In some embodiments, Compound 1 1,2-ethanedisulfonatehas an X-ray diffraction pattern comprising a characteristic peak indegrees 2θ at about 12.9°.

In some embodiments, Compound 1 1,2-ethanedisulfonate has an X-raydiffraction pattern comprising at least one characteristic peak indegrees 2θ selected from about 7.9°, about 10.5°, and about 12.9°.

In some embodiments, Compound 1 1,2-ethanedisulfonate has an X-raydiffraction pattern comprising characteristic peaks in degrees 2θselected from about 7.9°, about 10.5°, and about 12.9°.

In some embodiments, Compound 1 1,2-ethanedisulfonate has an X-raydiffraction pattern comprising at least four characteristic peaks indegrees 2θ selected from about 7.9°, about 10.5°, about 12.9°, about15.7°, about 17.6°, about 18.4°, about 20.3°, about 21.0°, and about23.7°. In some embodiments, Compound 1 1,2-ethanedisulfonate has anX-ray diffraction pattern comprising at least three characteristic peaksin degrees 2θ selected from about 7.9°, about 10.5°, about 12.9°, about15.7°, about 17.6°, about 18.4°, about 20.3°, about 21.0°, and about23.7°. In some embodiments, Compound 1 1,2-ethanedisulfonate has anX-ray diffraction pattern comprising at least two characteristic peaksin degrees 2θ selected from about 7.9°, about 10.5°, about 12.9°, about15.7°, about 17.6°, about 18.4°, about 20.3°, about 21.0°, and about23.7°. In some embodiments, Compound 1 1,2-ethanedisulfonate has anX-ray diffraction pattern comprising at least one characteristic peak indegrees 2θ selected from about 7.9°, about 10.5°, about 12.9°, about15.7°, about 17.6°, about 18.4°, about 20.3°, about 21.0°, and about23.7°.

In some embodiments, Compound 1 1,2-ethanedisulfonate has an X-raydiffraction pattern comprising at least four characteristic peaks indegrees 2θ selected from about 7.9°, about 10.5°, about 11.9°, about12.9°, about 15.7°, about 16.8°, about 17.6°, about 18.4°, about 19.4°,about 20.3°, about 21.0°, about 21.9°, about 23.7°, about 25.0°, andabout 25.8°. In some embodiments, Compound 1 1,2-ethanedisulfonate hasan X-ray diffraction pattern comprising at least three characteristicpeaks in degrees 2θ selected from about 7.9°, about 10.5°, about 11.9°,about 12.9°, about 15.7°, about 16.8°, about 17.6°, about 18.4°, about19.4°, about 20.3°, about 21.0°, about 21.9°, about 23.7°, about 25.0°,and about 25.8°. In some embodiments, Compound 1 1,2-ethanedisulfonatehas an X-ray diffraction pattern comprising at least two characteristicpeaks in degrees 2θ selected from about 7.9°, about 10.5°, about 11.9°,about 12.9°, about 15.7°, about 16.8°, about 17.6°, about 18.4°, about19.4°, about 20.3°, about 21.0°, about 21.9°, about 23.7°, about 25.0°,and about 25.8°. In some embodiments, Compound 1 1,2-ethanedisulfonatehas an X-ray diffraction pattern comprising at least one characteristicpeak in degrees 2θ selected from about 7.9°, about 10.5°, about 11.9°,about 12.9°, about 15.7°, about 16.8°, about 17.6°, about 18.4°, about19.4°, about 20.3°, about 21.0°, about 21.9°, about 23.7°, about 25.0°,and about 25.8°.

In some embodiments, Compound 1 1,2-ethanedisulfonate has an XRPDpattern with characteristic peaks as substantially shown in FIG. 33.

In some embodiments, Compound 1 1,2-ethanedisulfonate has a DSCthermogram characterized by an endotherm peak at a temperature of about190° C. and an exotherm peak at a temperature of about 221° C. In someembodiments, Compound 1 1,2-ethanedisulfonate has a DSC thermogramcharacterized by an endotherm peak at a temperature of about 190° C. Insome embodiments, Compound 1 1,2-ethanedisulfonate has a DSC thermogramcharacterized by an exotherm peak at a temperature of about 221° C. Insome embodiments, Compound 1 1,2-ethanedisulfonate has a DSC thermogramsubstantially as shown in FIG. 34.

In some embodiments, Compound 1 1,2-ethanedisulfonate has an X-raydiffraction pattern comprising at least four characteristic peaks indegrees 2θ selected from about 7.9°, about 10.5°, about 12.9°, about15.7°, about 17.6°, about 18.4°, about 20.3°, about 21.0°, and about23.7°; and Compound 1 1,2-ethanedisulfonate has a DSC thermogramcharacterized by an endotherm peak at a temperature of about 190° C. Insome embodiments, Compound 1 1,2-ethanedisulfonate has an X-raydiffraction pattern comprising at least four characteristic peaks indegrees 2θ selected from about 7.9°, about 10.5°, about 12.9°, about15.7°, about 17.6°, about 18.4°, about 20.3°, about 21.0°, and about23.7°; and Compound 1 1,2-ethanedisulfonate has a DSC thermogramcharacterized by an endotherm peak at a temperature of about 221° C.

In some embodiments, Compound 1 1,2-ethanedisulfonate can be isolatedwith a purity of at least about 80%, about 85%, about 90%, about 95%,about 96%, about 97%, about 98%, or about 99%. In some embodiments,Compound 1 1,2-ethanedisulfonate can be isolated with a purity greaterthan about 99%.

Compound 1 Sulfate

Provided herein is a solid form of Compound 1 sulfate, which isdescribed below in the Examples. In some embodiments, Compound 1 sulfateis amorphous.

Compound 1 sulfate can be prepared by any suitable method for thepreparation of sulfuric acid addition salts. For example, Compound 1 canbe combined with sulfuric acid (e.g., about 1.0 equiv or more) in asolvent and the resulting salt can be isolated by filtering the saltfrom solution. In some embodiments, the resulting salt is isolated ascrystalline Compound 1 sulfate. In certain embodiments, Compound 1 iscombined with about 1 to about 3 molar equivalents of sulfuric acid. Insome embodiments, Compound 1 is combined with about 1 to about 2 molarequivalents of sulfuric acid. In certain embodiments, Compound 1 iscombined with about 1.5 to about 2.5 molar equivalents of sulfuric acid.In certain embodiments, Compound 1 is combined with about 2.1 molarequivalents of sulfuric acid. In certain embodiments, the solvent is amixture of isopropanol, methanol, and dichloromethane. In certainembodiments, the solvent is a mixture of methanol and dichloromethane.In some embodiments, the solvent is a mixture of isopropanol anddichloromethane. In some embodiments, the solvent is methanol. In someembodiments, the solvent is isopropanol. In some embodiments, thesolvent is dichloromethane.

In some embodiments, Compound 1 sulfate can be isolated with a purity ofat least about 80%, about 85%, about 90%, about 95%, about 96%, about97%, about 98%, or about 99%. In some embodiments, Compound 1 sulfatecan be isolated with a purity greater than about 99%.

Compound 1 (Free Base)

Provided herein is a solid form of Compound 1.

Compound 1 can be prepared by treating an acid addition salt of Compound1 with a base. For example, Compound 1 di-HCl in a solvent be combinedwith sodium bicarbonate (e.g., about 2.0 equiv or more) and theresulting Compound 1 can be isolated by filtering the compound from thesolution. In certain embodiments, the acid addition salt is combinedwith about 2 to about 10 molar equivalents of sodium bicarbonate. Incertain embodiments, Compound 1 is combined with about 4 to about 8molar equivalents of sodium bicarbonate. In certain embodiments,Compound 1 is combined with about 5.5 molar equivalents of sodiumbicarbonate. In some embodiments, the solvent is a polar protic solvent.In some embodiments, the solvent is water.

In some embodiments, Compound 1 has an X-ray diffraction patterncomprising two characteristic peaks in degrees 2θ selected from about4.1° and about 21.7°. In some embodiments, Compound 1 has acharacteristic XRPD peak in degrees 2θ at about 4.1°. In someembodiments, Compound 1 has a characteristic XRPD peak in degrees 2θ atabout 21.7°. In some embodiments, Compound 1 has an X-ray diffractionpattern comprising two characteristic peaks in degrees 2θ selected fromabout 4.1° and about 21.7°.

In some embodiments, Compound 1 has an XRPD pattern with characteristicpeaks as substantially shown in FIG. 37.

In some embodiments, Compound 1 has a DSC thermogram characterized by anendotherm peak at a temperature of about 159° C. In some embodiments,Compound 1 has a DSC thermogram substantially as shown in FIG. 38. Insome embodiments, Compound 1 has a TGA thermogram substantially as shownin FIG. 39.

In some embodiments, Compound 1 has an X-ray diffraction patterncomprising two characteristic peaks in degrees 2θ selected from about4.1° and about 21.7°; and Compound 1 has a DSC thermogram characterizedby an endotherm peak at a temperature of about 159° C.

In some embodiments, Compound 1 can be isolated with a purity of atleast about 80%, about 85%, about 90%, about 95%, about 96%, about 97%,about 98%, or about 99%. In some embodiments, Compound 1 can be isolatedwith a purity greater than about 99%.

Processes for Preparing Compound 1 or a Salt Thereof

Provided herein are also processes for preparing Compound 1 or a saltthereof. The processes for preparing Compound 1 or a salt thereofprovided herein have certain advantages over the processes currentlydisclosed in the art. For example, the processes described hereindemonstrate good scalability and yields. In addition, the keyintermediates of the disclosed processes contain chromophores, and theirreaction progresses are easily monitored by HPLC.

The processes for preparing Compound 1 or a salt thereof can comprise:

-   -   a) treating Compound 11 having the formula:

-   -   -   with HCl to form Compound 10 having the formula:

-   -   b) treating Compound 10 with B3 and by tert-butyl        chlorosulfonylcarbamate, wherein B3 is a base, to form Compound        9 having the formula:

-   -   c) treating Compound 9 with A3, wherein A3 is an acid, to form        Compound 4 having the formula:

-   -   d) contacting piperidin-4-one hydrochloride hydrate with        2,2,2-trifluoroacetic anhydride in the presence of B2, wherein        B2 is a base, to form Compound 7 having the formula:

-   -   e) contacting Compound 7 with Compound 8 having the formula:

-   -   -   in the presence of A2 and RA1, wherein A2 is an acid, and            RA1 is a reducing agent, to provide Compound 6 having the            formula:

-   -   f) reacting Compound 6 with di-tert-butyl dicarbonate to produce        Compound 5 having the formula:

-   -   g) treating Compound 5 with B 1, wherein B1 is a base, to        produce Compound 3 having the formula:

-   -   h) contacting Compound 3 with Compound 4 to form Compound 2        having the formula:

and

-   -   i) deprotecting Compound 2 with A1, wherein A1 is an acid, to        form Compound 1.

The process to prepare Compound 1 can include deprotecting Compound 2with A1, wherein A1 is an acid. The acid can be a mineral acid. In someembodiments, A1 is HCl. The salt of Compound 1 can be a hydrochloricacid salt. The salt of Compound 1 can be a dihydrochloric acid salt. Thedeprotecting can be performed in the presence of S1, wherein S1 is aprotic solvent. In some embodiments, S1 is an alcohol, e.g., methanol.In some embodiments, the deprotecting is performed at a temperaturebetween about 30° C. to about 50° C. In some embodiments, thedeprotecting is performed at a temperature of about 35° C. to about 45°C., e.g., about 40° C. In some embodiments, the deprotecting comprisesusing about 1 to about 15 molar equivalents of A1 to Compound 2. In someembodiments, the protecting comprises using about 5 to about 10 molarequivalents of A1 to Compound 2. In some embodiments, the protectingcomprises using about 8 to about 9 molar equivalents of A1 to Compound2.

The process of preparing Compound 1 can further include precipitatingCompound 1 from a solution comprising Compound 1 and S2, wherein S2comprises a solvent and an anti-solvent. The solvent can be a polaraprotic solvent, e.g., 2-butanone. The anti-solvent can be a hydrocarbonsolvent, e.g., heptane.

Compound 2 can be prepared by a process that includes contactingCompound 3 with Compound 4. The contacting of Compound 3 and Compound 4can be performed in the presence of S3, wherein S3 is a polar proticsolvent. In some embodiments, S3 is an alcohol, e.g., methanol. In someembodiments, the contacting of Compound 3 and Compound 4 is performed ata temperature of about 55° C. to about 65° C. For example, thetemperature is about 60° C. In some embodiments, the contacting ofCompound 3 and Compound 4 comprises using about 1 to about 2 molarequivalents of Compound 4 per molar equivalent of Compound 3. In someembodiments, the contacting of Compound 3 and Compound 4 comprises usingabout 1.1 to about 1.5 molar equivalents of Compound 4 per molarequivalent of Compound 3. In some embodiments, the contacting ofCompound 3 and Compound 4 comprises using about 1.15 molar equivalentsof Compound 4 per molar equivalent of Compound 3.

Compound 3 can be produced by a process that includes treating Compound5 with B 1, wherein B1 is a base. In some embodiments, B1 is a metalhydroxide base, e.g., KOH. The treating of Compound 5 can be performedat a temperature of about 50° C. to about 60° C., e.g., about 55° C. Insome embodiments, the treating of Compound 5 is performed in thepresence of S4, wherein S4 is a polar protic solvent. In someembodiments, S4 is an alcohol, e.g., methanol. In some embodiments, thetreating of Compound 5 comprises using about 1 to about 5 molarequivalents of B1 per molar equivalent of Compound 5. In someembodiments, the treating of Compound 5 comprises using about 3 molarequivalents of B1 per molar equivalent of Compound 5.

Compound 5 can be produced by a process comprising reacting Compound 6with di-tert-butyl dicarbonate. The reacting of Compound 6 can beperformed in the presence of S5, wherein S5 is a polar aprotic solvent.In some embodiments, S5 is dichloromethane. In some embodiments, thereacting of Compound 6 is performed at about 35° C. to about 45° C. Insome embodiments, the reacting of Compound 6 is performed at about 40°C. In some embodiments, the reacting of Compound 6 comprises using about1 to about 1.5 molar equivalents of di-tert-butyl dicarbonate per molarequivalent of Compound 6. In some embodiments, the reacting of Compound6 comprises using about 1 to about 1.25 molar equivalents ofdi-tert-butyl dicarbonate per molar equivalent of Compound 6. In someembodiments, the reacting of Compound 6 comprises using about 1 (e.g.,about 1.1) molar equivalents of di-tert-butyl dicarbonate per molarequivalent of Compound 6.

Compound 6 can be produced by a process comprising contacting a Compound7 with Compound 8. In some embodiments, in the presence of A2 and RA1,wherein A2 is an acid and RA1 is a reducing agent. A2 can be an organicacid, e.g., acetic acid. In some embodiments, about 0.75 to 1.25 molarequivalents of Compound 8 are used per molar equivalent of Compound 7.In some embodiments, about 1.1 molar equivalents of Compound 8 are usedper molar equivalent of Compound 7. In some embodiments, about 1 toabout 3 molar equivalents of A2 are used per molar equivalent ofCompound 7. In some embodiments, about 1.5 to about 2.5 molarequivalents of A2 are used per molar equivalent of Compound 7. In someembodiments, about 2 (e.g., about 2.1) molar equivalents of A2 are usedper molar equivalent of Compound 7. In some embodiments, RA1 is aborohydride reducing agent. In some embodiments, RA1 is sodiumtriacetoxyborohydride. In some embodiments, about 1 to about 2 molarequivalents of RA1 are used per molar equivalent of Compound 7. In someembodiments, about 1.2 molar equivalents of RA1 are used per molarequivalent of Compound 7. In some embodiments, the contacting ofCompound 7 with Compound 8 is performed in the presence of S6, whereinS6 is a polar aprotic solvent. In some embodiments, S6 isdichloromethane. In some embodiments, the contacting of Compound 7 withCompound 8 is performed at first temperature and then cooled to secondtemperature. In some embodiments, the first temperature is about 20° C.to about 30° C. In some embodiments, the first temperature is roomtemperature. In some embodiments, the second temperature is betweenabout −5° C. and about 5° C. In some embodiments, the second temperatureis about 5° C.

Compound 7 can be produced by a process comprising contactingpiperidin-4-one hydrochloride hydrate with 2,2,2-trifluoroaceticanhydride in the presence of B2, wherein B2 is a base. In someembodiments, B2 is an amine base. In some embodiments, B2 istriethylamine. In some embodiments, the contacting of piperidin-4-onehydrochloride hydrate with 2,2,2-trifluoroacetic anhydride is performedin the presence of S7, wherein S7 is a polar aprotic solvent. In someembodiments, S7 is dichloromethane. In some embodiments, between about 1to about 2 molar equivalents of B2 are used per molar equivalent ofpiperidin-4-one hydrochloride hydrate. In some embodiments, about 1(e.g., about 1.1) molar equivalents of B2 are used per molar equivalentof piperidin-4-one hydrochloride hydrate. In some embodiments, betweenabout 1 to about 3 molar equivalents of 2,2,2-trifluoroacetic anhydrideare used per molar equivalent of piperidin-4-one hydrochloride hydrate.In some embodiments, about 2 molar equivalents of 2,2,2-trifluoroaceticanhydride are used per molar equivalent of piperidin-4-one hydrochloridehydrate. In some embodiments, the contacting of piperidin-4-onehydrochloride hydrate with 2,2,2-trifluoroacetic anhydride is performedat a temperature between about 0° C. and about 30° C.

Compound 4 can be produced by a process comprising treating Compound 9with A3, wherein A3 is an acid. In some embodiments, A3 is an organicacid such as trifluoroacetic acid. In some embodiments, the treating ofCompound 9 is performed in the presence of S8, wherein S8 is a polaraprotic solvent, e.g., dichloromethane. In some embodiments, betweenabout 2 to about 10 molar equivalents of A3 are used per molarequivalent of Compound 9. In some embodiments, between about 3 to about6 molar equivalents of A3 are used per molar equivalent of Compound 9.In some embodiments, about 4 molar equivalents of A3 are used per molarequivalent of Compound 9. In some embodiments, the treating of Compound9 is performed at a temperature between about 25° C. and about 45° C. Insome embodiments, the treating of Compound 9 is performed at atemperature between about 30° C. and 40° C.

Compound 9 can be produced by a process comprising treating Compound 10with B3 and tert-butyl chlorosulfonylcarbamate, wherein B3 is a base. Insome embodiments, B3 is an amine base, e.g., triethylamine. In someembodiments, between about 1 and about 5 molar equivalents of B3 areused per molar equivalent of Compound 10. In some embodiments, betweenabout 2 and about 3 molar equivalents of B3 are used per molarequivalent of Compound 10. In some embodiments, wherein the treating ofCompound 10 is performed in the presence of S9, wherein S9 is a polaraprotic solvent. In some embodiments, S9 is dichloromethane. In someembodiments, the treating of Compound 10 is performed at a firsttemperature and then cooled to a second temperature. In someembodiments, the first temperature is between about 15° C. and about 30°C. In some embodiments, the first temperature is room temperature. Insome embodiments, the second temperature is between about −5° C. andabout 5° C. In some embodiments, the second temperature is about 0° C.

Compound 10 can be produced by a process comprising treating Compound 11with HCl. In some embodiments, the treating of Compound 11 is performedin the presence of S10, wherein S10 is a polar aprotic solvent, e.g.,dichloromethane. In some embodiments, between about 1 and about 20 molarequivalents of HCl are used per molar equivalent of Compound 11. In someembodiments, between about 5 and about 15 molar equivalents of HCl areused per molar equivalent of Compound 11. In some embodiments, about 10molar equivalents of HCl are used per molar equivalent of Compound 11.

Compound 1 or a salt thereof can also be prepared by a process thatincludes:

-   -   a) contacting Compound 16 having the formula:

-   -   -   with A6 and water, wherein A6 is an acid, to produce            Compound 15 having the formula:

-   -   b) treating Compound 15 with B5 and tert-butyl        chlorosulfonylcarbamate, wherein B5 is a base, to produce        Compound 14 having the formula:

-   -   c) contacting a Compound 14 with Compound 8 having the formula:

-   -   -   in the presence of A5 and RA2, wherein A5 is an acid, and            RA2 is a reducing agent to produce Compound 13 having the            formula:

-   -   d) contacting Compound 13 with di-tert-butyl dicarbonate to        produce Compound 12 having the formula:

and

-   -   e) deprotecting Compound 12 with A4, wherein A4 is an acid, to        form Compound 1.

Compound 1 or a salt thereof can be prepared by a process that includesdeprotecting Compound 12 with A4, wherein A4 is an acid. In someembodiments, A4 is a mineral acid. For example, A4 is HCl. The salt ofCompound 1 can be a hydrochloric acid salt. In some embodiments, thedeprotecting of Compound 12 is performed in the presence of S11, whereinS11 is a polar protic solvent. In some embodiments, S11 is an alcohol,e.g., methanol. In some embodiments, the deprotecting of Compound 12 isperformed at a temperature between about 35° C. and about 45° C. In someembodiments, the deprotecting of Compound 12 is performed at atemperature of about 40° C. In some embodiments, the process ofpreparing Compound 1 further comprises precipitating Compound 1 from asolution comprising Compound 1 and S12, wherein S12 comprises a solventand an anti-solvent. In some embodiments, the solvent of S12 is a polaraprotic solvent, e.g., 2-butanone. In some embodiments, the anti-solventof S12 is a hydrocarbon solvent, e.g., heptane. In some embodiments, thedeprotecting of Compound 12 comprises using about 1 to about 15 molarequivalents of A4 per molar equivalent of Compound 12. In someembodiments, the deprotecting of Compound 12 comprises using about 5 toabout 10 molar equivalents of A4 per molar equivalent of Compound 12. Insome embodiments, the deprotecting of Compound 12 comprises using about8 to about 9 molar equivalents of A4 per molar equivalent of Compound12.

Compound 12 can be prepared by a process comprising contacting Compound3 with Compound 9 in the presence of B4, wherein B4 is a base. In someembodiments, B4 is an amine base. In some embodiments, B4 is1,8-diazabicyclo[5.4.0]undec-7-ene. In some embodiments, the contactingof Compound 3 with Compound 9 is performed in the presence of S13,wherein S13 is a polar aprotic solvent. In some embodiments, S13 isacetonitrile. In some embodiments, the contacting of Compound 3 withCompound 9 is performed at a temperature between about 50° C. and about60° C. In some embodiments, the contacting of Compound 3 with Compound 9is performed at a temperature of about 55° C. In some embodiments, thecontacting of Compound 3 with Compound 9 comprises using between about 1and about 5 molar equivalents of Compound 3 per molar equivalent ofCompound 9. In some embodiments, the contacting of Compound 3 withCompound 9 comprises using between about 1 and about 2 molar equivalentsof Compound 3 per molar equivalent of Compound 9. In some embodiments,the contacting of Compound 3 with Compound 9 comprises using about 1.5equivalents of Compound 3 per equivalent of molar Compound 9. In someembodiments, the contacting of Compound 3 with Compound 9 comprisesusing between about 1 and about 1.5 molar equivalents of B4 per molarequivalent of Compound 9. In some embodiments, the contacting ofCompound 3 with Compound 9 comprises using about 1 (e.g., about 1.1)molar equivalents of B4 per molar equivalent of Compound 9.

Alternatively, Compound 12 can be prepared by a process comprisingcontacting Compound 13 with di-tert-butyl dicarbonate. In someembodiments, the reacting of Compound 13 is performed in the presence ofS14, wherein S14 is a polar aprotic solvent, e.g., dichloromethane. Insome embodiments, the reacting of Compound 13 is performed at atemperature between about 35° C. and about 45° C. In some embodiments,the reacting of Compound 13 is performed at about 40° C. In someembodiments, the reacting of Compound 13 comprises using between about 1and about 2 molar equivalents of di-tert-butyl dicarbonate per molarequivalent of Compound 13. In some embodiments, the reacting of Compound13 comprises using about 1 and about 1.25 molar equivalents ofdi-tert-butyl dicarbonate per molar equivalent of Compound 13. In someembodiments, the reacting of Compound 13 comprises using about 1 molarequivalent of di-tert-butyl dicarbonate per molar equivalent of Compound13.

Compound 13 can be prepared by a process comprising contacting aCompound 14 with Compound 8 in the presence of A5 and RA2, wherein A5 isan acid, and RA2 is a reducing agent. In some embodiments, A5 is anorganic acid. In some embodiments, A5 is acetic acid. In someembodiments, the contacting of Compound 14 with Compound 8 comprisesusing between about 1 and about 3 molar equivalents of A5 per molarequivalent Compound 14. In some embodiments, the contacting of Compound14 with Compound 8 comprises using about 1.2 molar equivalents of A5 permolar equivalent of Compound 14. In some embodiments, the contacting ofCompound 14 with Compound 8 is performed in the presence of S15, whereinS15 is a polar aprotic solvent. In some embodiments, S15 isdichloromethane. In some embodiments, the contacting of Compound 14 withCompound 8 is performed at a first temperature and then cooled to asecond temperature. In some embodiments, the first temperature isbetween about 20° C. and about 30° C. In some embodiments, the firsttemperature is room temperature. In some embodiments, the secondtemperature is between about −5° C. and about 5° C. In some embodiments,the second temperature is about 0° C. In some embodiments, RA2 is aborohydride reducing agent. In some embodiments, RA2 is sodiumtriacetoxyborohydride. In some embodiments, the contacting of Compound14 with Compound 8 comprises using between about 1 and about 3 molarequivalents of RA2 per molar equivalent of Compound 14. In someembodiments, the contacting of Compound 14 with Compound 8 comprisesusing about 1.2 molar equivalents of RA2 per molar equivalent ofCompound 14.

Compound 14 can be prepared by a process comprising: treating Compound15 with B5 and tert-butyl chlorosulfonylcarbamate, wherein B5 is a base.In some embodiments, B5 is an amine base. In some embodiments, B5 istriethylamine. In some embodiments, between about 1 and about 5 molarequivalents of B5 are used per molar equivalent of Compound 15. In someembodiments, between about 2 and about 3 molar equivalents of B5 areused per molar equivalent of Compound 15. In some embodiments, thetreating of Compound 15 is performed in the presence of S16, wherein S16is a polar aprotic solvent. In some embodiments, S16 is dichloromethane.In some embodiments, the treating of Compound 15 is performed at a firsttemperature and then cooled to a second temperature. In someembodiments, the first temperature is between about 15° C. and about 30°C. In some embodiments, the first temperature is room temperature. Insome embodiments, the second temperature is between about −5° C. andabout 5° C. In some embodiments, the second temperature is about 0° C.

Compound 15 can be prepared by a process comprising: contacting Compound16 with A6 and water, wherein A6 is an acid. In some embodiments, A6 isa mineral acid. In some embodiments, A6 is HCl. In some embodiments, A6is a solution of HCl in isopropanol. In some embodiments, the contactingof Compound 16 is performed in the presence of S17, wherein S17 is apolar protic solvent. In some embodiments, S17 is an alcohol. In someembodiments, S17 is isopropanol. In some embodiments, the contacting ofCompound 16 is performed at a temperature between about 55° C. and about65° C. In some embodiments, the contacting of Compound 16 is performedat about 60° C.

Compound 16 can be prepared by a process comprising: contactingtert-butyl 3-(cyanomethylene) azetidine-1-carboxylate with1,4-dioxa-8-azaspiro[4.5]decane. In some embodiments, the contacting oftert-butyl 3-(cyanomethylene) azetidine-1-carboxylate with1,4-dioxa-8-azaspiro[4.5]decane is performed in the presence of S18,wherein S18 is a polar protic solvent. In some embodiments, S18 is analcohol. In some embodiments, S18 is methanol. In some embodiments, thecontacting of tert-butyl 3-(cyanomethylene) azetidine-1-carboxylate with1,4-dioxa-8-azaspiro[4.5]decane is performed at a temperature betweenabout 60° C. and about 70° C. In some embodiments, the contacting oftert-butyl 3-(cyanomethylene) azetidine-1-carboxylate with1,4-dioxa-8-azaspiro[4.5]decane is performed at a temperature of about65° C.

In some embodiments, provided herein is a process for preparing Compound1 comprising deprotecting Compound 2 with A1, wherein A1 is an acid, toform Compound 1. In some embodiments, provided herein is a process forpreparing Compound 1 comprising:

-   -   a) contacting Compound 3 with Compound 4 to form Compound 2; and    -   b) deprotecting Compound 2 with A1, wherein A1 is an acid, to        form Compound 1.

In some embodiments, provided herein is a process for preparing Compound1 comprising contacting deprotecting Compound 12 with A4, wherein A4 isan acid to form Compound 1. In some embodiments, provided herein is aprocess for preparing Compound 1 comprising:

-   -   a) contacting Compound 3 with Compound 9 in the presence of B4,        wherein B4 is a base, to form Compound 12; and    -   b) deprotecting Compound 12 with A4, wherein A4 is an acid to        form Compound 1.

In some embodiments, provided herein is a process for preparing Compound1 comprising:

-   -   a) contacting Compound 13 with di-tert-butyl dicarbonate to form        Compound 12; and    -   b) deprotecting Compound 12 with A4, wherein A4 is an acid.

In some embodiments, provided herein is a process for preparing Compound1 comprising:

-   -   a) contacting Compound 14 with Compound 8 in the presence of A5        and RA2, wherein A5 is an acid, and RA2 is a reducing agent to        produce Compound 13;    -   b) contacting Compound 13 with di-tert-butyl dicarbonate to form        Compound 12; and    -   c) deprotecting Compound 12 with A4, wherein A4 is an acid.

In some embodiments, provided herein is a process for preparing Compound2, comprising contacting Compound 3 with Compound 4. In someembodiments, provided herein is a process for preparing Compound 2,comprising:

-   -   a) treating Compound 11 with HCl to form Compound 10;    -   b) treating Compound 10 with B3 and tert-butyl        chlorosulfonylcarbamate, wherein B3 is a base, to form Compound        9;    -   c) treating Compound 9 with A3, wherein A3 is an acid, to form        Compound 4;    -   d) contacting piperidin-4-one hydrochloride hydrate with        2,2,2-trifluoroacetic anhydride in the presence of B2, wherein        B2 is a base, to form Compound 7;    -   e) contacting Compound 7 with Compound 8 in the presence of A2        and RA1, wherein A2 is an acid, and RA1 is a reducing agent, to        provide Compound 6;    -   f) reacting Compound 6 with di-tert-butyl dicarbonate to produce        Compound 5;    -   g) treating Compound 5 with B1, wherein B1 is a base, to produce        Compound 3; and    -   h) contacting Compound 3 with Compound 4 to form Compound 2.

In some embodiments, provided herein is a process for preparing Compound12 comprising contacting Compound 13 with di-tert-butyl dicarbonate. Insome embodiments, provided herein is a process for preparing Compound 12comprising contacting Compound 3 with Compound 9 in the presence of B4,wherein B4 is a base.

In some embodiments, provided herein is a process for preparing Compound9 comprising treating Compound 10 with B3 and tert-butylchlorosulfonylcarbamate, wherein B3 is a base. In some embodiments,provided herein is a process for preparing Compound 9 comprising:

-   -   a) treating Compound 11 with HCl to form Compound 10; and    -   b) treating Compound 10 with B3 and tert-butyl        chlorosulfonylcarbamate, wherein B3 is a base, to form Compound        9.

Also provided herein is also a process for preparing Compound 4comprising:

-   -   a) treating Compound 10 with B3 and tert-butyl        chlorosulfonylcarbamate, wherein B3 is a base, to form Compound        9; and    -   b) treating Compound 9 with A3, wherein A3 is an acid, to form        Compound 4.

In some embodiments, Compound 4 is prepared by a process comprising:

-   -   c) treating Compound 11 with HCl to form Compound 10;    -   d) treating Compound 10 with B3 and tert-butyl        chlorosulfonylcarbamate, wherein B3 is a base, to form Compound        9; and    -   e) treating Compound 9 with A3, wherein A3 is an acid, to form        Compound 4.

Also provided herein is a process for preparing Compound 3 comprisingtreating Compound 5 with B1, wherein B1 is a base, to produce Compound3. In some embodiments, Compound 3 is prepared by a process comprising:

-   -   a) reacting Compound 6 with di-tert-butyl dicarbonate to produce        Compound 5; and    -   b) treating Compound 5 with B1, wherein B1 is a base, to produce        Compound 3.

In some embodiments, Compound 3 is prepared by a process comprising:

-   -   a) contacting Compound 7 with Compound 8 in the presence of A2        and RA1, wherein A2 is an acid, and RA1 is a reducing agent, to        provide Compound 6;    -   b) reacting Compound 6 with di-tert-butyl dicarbonate to produce        Compound 5; and    -   c) treating Compound 5 with B1, wherein B1 is a base, to produce        Compound 3.

Also provided herein is a process for preparing Compound 3 comprising:

-   -   a) contacting piperidin-4-one hydrochloride hydrate with        2,2,2-trifluoroacetic anhydride in the presence of B2, wherein        B2 is a base, to form Compound 7;    -   b) contacting Compound 7 with Compound 8 in the presence of A2        and RA1, wherein A2 is an acid, and RA1 is a reducing agent, to        provide Compound 6;    -   c) reacting Compound 6 with di-tert-butyl dicarbonate to produce        Compound 5; and    -   d) treating Compound 5 with B1, wherein B1 is a base, to produce        Compound 3.

In some embodiments, provided herein is a process for preparing Compound14 comprising treating Compound 15 with B5 and tert-butylchlorosulfonylcarbamate, wherein B5 is a base, to provide Compound 14.In some embodiments, provided herein is a process for preparing Compound14 comprising:

-   -   a) contacting tert-butyl 3-(cyanomethyl ene)        azetidine-1-carboxylate with 1,4-dioxa-8-azaspiro[4.5]decane to        provide Compound 16; and    -   b) contacting Compound 16 with A6, wherein A6 is an acid, and        water to provide Compound 15.

In some embodiments, provided herein is a process for preparing Compound14 comprising:

-   -   a) contacting tert-butyl 3-(cyanomethylene)        azetidine-1-carboxylate with 1,4-dioxa-8-azaspiro[4.5]decane to        provide Compound 16;    -   b) contacting Compound 16 with A6, wherein A6 is an acid, and        water to provide Compound 15;    -   c) treating Compound 15 with B5 and tert-butyl        chlorosulfonylcarbamate, wherein B5 is a base, to provide        Compound 14.

In some embodiments, provided herein is a compound having the formula:

or a salt thereof.

In some embodiments, provided herein is a compound having the formula:

or a salt thereof.

In some embodiments, provided herein is a compound having the formula:

or a salt thereof.

In some embodiments, provided herein is a compound having the formula:

or a salt thereof.

In some embodiments, provided herein is a compound having the formula:

or a salt thereof.

In some embodiments, provided herein is a compound having the formula:

or a salt thereof.

In some embodiments, provided herein is a compound having the formula:

or a salt thereof.

In some embodiments, provided herein is a compound having the formula:

or a salt thereof.

In some embodiments, provided herein is a compound having the formula:

or a salt thereof.

In some embodiments, provided herein is a compound having the formula:

or a salt thereof.

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, can also beprovided in combination in a single embodiment (while the embodimentsare intended to be combined as if written in multiply dependent form).Conversely, various features of the invention which are, for brevity,described in the context of a single embodiment, can also be providedseparately or in any suitable subcombination.

As used herein, the term “reacting,” “contacting” or “treating” whendescribing a certain process is used as known in the art and generallyrefers to the bringing together of chemical reagents in such a manner soas to allow their interaction at the molecular level to achieve achemical or physical transformation. In some embodiments, the reactinginvolves two reagents, wherein one or more equivalents of second reagentare used with respect to the first reagent. The reacting steps of theprocesses described herein can be conducted for a time and underconditions suitable for preparing the identified product.

The terms “protecting” and “deprotecting” as used herein in a chemicalreaction refer to inclusion of a chemical group in a process and suchgroup is removed in a later step in the process. The term preparation ofCompound 1 and its salts can involve the protection and deprotection ofvarious chemical groups. The need for protection and deprotection, andthe selection of appropriate protecting groups, can be readilydetermined by one skilled in the art. The chemistry of protecting groupsis described, e.g., in Kocienski, Protecting Groups, (Thieme, 2007);Robertson, Protecting Group Chemistry, (Oxford University Press, 2000);Smith et al., March's Advanced Organic Chemistry: Reactions, Mechanisms,and Structure, 6^(th) Ed. (Wiley, 2007); Peturssion et al., “ProtectingGroups in Carbohydrate Chemistry,” J. Chem. Educ., 1997, 74(11), 1297;and Wuts et al., Protective Groups in Organic Synthesis, 4th Ed.,(Wiley, 2006). Examples of protecting groups include amino protectinggroups. As used herein, “amino protecting group” refers to anyprotecting group for the protection of amines. Example amino protectinggroups include, but are not limited to, phenylsulfonyl,benzyloxycarbonyl (Cbz), 2,2,2-trichloroethoxycarbonyl (Troc),2-(trimethylsilyl)ethoxycarbonyl (Teoc),2-(4-trifluoromethylphenylsulfonyl)ethoxycarbonyl (Tsc),t-butoxycarbonyl (BOC), 1-adamantyloxycarbonyl (Adoc),2-adamantylcarbonyl (2-Adoc), 2,4-dimethylpent-3-yloxycarbonyl (Doc),cyclohexyloxycarbonyl (Hoc), 1,1-dimethyl-2,2,2-trichloroethoxycarbonyl(TcBOC), vinyl, 2-chloroethyl, 2-phenylsulfonylethyl, allyl, benzyl,2-nitrobenzyl, 4-nitrobenzyl, diphenyl-4-pyridylmethyl,N′,N′-dimethylhydrazinyl, methoxymethyl, t-butoxymethyl (Bum),benzyloxymethyl (BOM), or 2-tetrahydropyranyl (THP), tri(C₁₋₄alkyl)silyl (e.g., tri(isopropyl)silyl), 1,1-diethoxymethyl, orN-pivaloyloxymethyl (POM).

As used herein, the phrase “metal hydroxide base,” employed alone or incombination with other terms, refers to a base having formula MOH,wherein M refers to a metal such as an alkali metal (e.g. lithium,sodium, or potassium). Example alkali metal hydroxide bases include, butare not limited to lithium hydroxide, sodium hydroxide, and potassiumhydroxide.

The term “amine base” refers to a base that has an amine group. Theamine can be a primary, secondary, or tertiary amine. Examples of anamine base include methylamine, dimethylamine, diphenyl amine,trimethylamine, triethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, andthe like.

The term “mineral acid” refers to an acid that is formed from inorganiccompound and can form hydrogen ions and conjugate base ions in anaqueous solution. Mineral acids can be a strong acid or strong acid.Examples of mineral acids include but not limited to hydrochloric acid,perchloric acid, sulfuric acid, nitric acid, boric acid, phosphoricacid, and the like.

The term “organic acid” refers to an acid with an organic moiety.Examples of organic acid include but not limited to acetic acid,trifluoroacetic acid, formic acid, benzoic acid, toluenesulfonic acid,triflic acid, and the like.

In some embodiments, anti-solvent as described herein refers to asolvent where Compound 1 or its salts are less soluble relative toanother solvent or solvent mixture in the solution. For example,anti-solvent can include but not limited to benzene, cyclohexane,pentane, hexane, heptane (e.g., n-heptane), toluene, cycloheptane,methylcyclohexane, heptane, ethylbenzene, m-, o-, or p-xylene, octane,indane, nonane, or naphthalene.

The reactions of the processes described herein can be carried out insuitable solvents which can be readily selected by one of skill in theart of organic synthesis. Suitable solvents can be substantiallynonreactive with the starting materials (reactants), the intermediates,or products at the temperatures at which the reactions are carried out,e.g., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature. A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected. In some embodiments, reactionscan be carried out in the absence of solvent, such as when at least oneof the reagents is a liquid or gas.

Suitable solvents can include halogenated solvents such as carbontetrachloride, bromodichloromethane, dibromochloromethane, bromoform,chloroform, bromochloromethane, dibromomethane, butyl chloride,dichloromethane (methylene chloride), tetrachloroethylene,trichloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane,1,1-dichloroethane, 2-chloropropane, α,α,α-trifluorotoluene,1,2-dichloroethane, 1,2-dibromoethane, hexafluorobenzene,1,2,4-trichlorobenzene, 1,2-dichlorobenzene, chlorobenzene,fluorobenzene, mixtures thereof and the like.

Suitable ether solvents include: dimethoxymethane, tetrahydrofuran,1,3-dioxane, 1,4-dioxane, furan, tetrahydrofuran (THF), diethyl ether,ethylene glycol dimethyl ether, ethylene glycol diethyl ether,diethylene glycol dimethyl ether (diglyme), diethylene glycol diethylether, triethylene glycol dimethyl ether, anisole, tert-butyl methylether, mixtures thereof and the like.

Suitable polar protic solvents can include, by way of example andwithout limitation, water, methanol, ethanol, 2-nitroethanol,2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1-propanol,2-propanol, 2-methoxyethanol, 1-butanol, 2-butanol, iso-butyl alcohol,tert-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or3-pentanol, neo-pentyl alcohol, tert-pentyl alcohol, diethylene glycolmonomethyl ether, diethylene glycol monoethyl ether, cyclohexanol,benzyl alcohol, phenol, or glycerol. The polar protic solvent can be analcohol such as methanol, ethanol, 1-propanol, 2-propanol, and the like.

Suitable aprotic solvents can include, by way of example and withoutlimitation, 2-butanone, acetonitrile, dichloromethane,N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA),1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU),1,3-dimethyl-2-imidazolidinone (DMI), N-methylpyrrolidinone (NMP),formamide, N-methylacetamide, N-methylformamide, acetonitrile, dimethylsulfoxide, propionitrile, ethyl formate, methyl acetate,hexachloroacetone, acetone, ethyl methyl ketone, ethyl acetate,sulfolane, N,N-dimethylpropionamide, tetramethylurea, nitromethane,nitrobenzene, hexamethylphosphoramide, and the like.

Suitable hydrocarbon solvents include benzene, cyclohexane, pentane,hexane, toluene, cycloheptane, methylcyclohexane, heptane, ethylbenzene,m-, o-, or p-xylene, octane, indane, nonane, or naphthalene.

The term “reducing agent” as used herein refers to a compound thatdonates an electron to another compound in a redox reaction. Thereducing agent would be oxidized after it loses its electrons. Examplesof reducing agents include, but not limited to, borohydride,triacetoxyborohydride, sodium borohydride, lithium aluminium hydride,hydrogen on palladium, and the like.

The reactions of the processes described herein can be carried out inair or under an inert atmosphere. Typically, reactions containingreagents or products that are substantially reactive with air can becarried out using air-sensitive synthetic techniques that are well knownto the skilled artisan.

The processes described herein can be monitored according to anysuitable method known in the art. For example, product formation can bemonitored by spectroscopic means, such as nuclear magnetic resonancespectroscopy (e.g., ¹H or ¹³C), infrared spectroscopy, spectrophotometry(e.g., UV-visible), or mass spectrometry; or by chromatography such ashigh performance liquid chromatography (HPLC) or thin layerchromatography. The compounds obtained by the reactions can be purifiedby any suitable method known in the art. For example, chromatography(medium pressure) on a suitable adsorbent (e.g., silica gel, alumina andthe like), HPLC, or preparative thin layer chromatography; distillation;sublimation, trituration, or recrystallization. The purity of thecompounds, in general, are determined by physical methods such asmeasuring the melting point (in case of a solid), obtaining a NMRspectrum, or performing a HPLC separation. If the melting pointdecreases, if unwanted signals in the NMR spectrum are decreased, or ifextraneous peaks in an HPLC trace are removed, the compound can be saidto have been purified. In some embodiments, the compounds aresubstantially purified.

The expressions, “ambient temperature” and “room temperature,” as usedherein, are understood in the art, and refer generally to a temperature,e.g., a reaction temperature, that is about the temperature of the roomin which the reaction is carried out, for example, a temperature fromabout 20° C. to about 30° C.

Methods of Use

Compounds and solid forms of the invention, e.g., Compound 1 and saltsthereof, are LSD1 inhibitors and, thus, are useful in treating diseasesand disorders associated with activity of LSD1. For the uses describedherein, any of the compounds and solid forms of the invention, includingany of the embodiments thereof, may be used.

In some embodiments, the compounds of the invention are selective forLSD1 over LSD2, meaning that the compounds bind to or inhibit LSD1 withgreater affinity or potency, compared to LSD2. In general, selectivitycan be at least about 5-fold, at least about 10-fold, at least about20-fold, at least about 50-fold, at least about 100-fold, at least about200-fold, at least about 500-fold or at least about 1000-fold.

As inhibitors of LSD1, the compounds and solid forms of the inventionare useful in treating LSD1-mediated diseases and disorders. The term“LSD1-mediated disease” or “LSD1-mediated disorder” refers to anydisease or condition in which LSD1 plays a role, or where the disease orcondition is associated with expression or activity of LSD1. Thecompounds of the invention can therefore be used to treat or lessen theseverity of diseases and conditions where LSD1 is known to play a role.

Diseases and conditions treatable using the compounds and solid forms ofthe invention include generally cancers, inflammation, autoimmunediseases, viral induced pathogenesis, beta-globinopathies, and otherdiseases linked to LSD1 activity.

Cancers treatable using compounds according to the present inventioninclude, for example, hematological cancers, sarcomas, lung cancers,gastrointestinal cancers, genitourinary tract cancers, liver cancers,bone cancers, nervous system cancers, gynecological cancers, and skincancers.

Example hematological cancers include, for example, lymphomas andleukemias such as acute lymphoblastic leukemia (ALL), acute myelogenousleukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocyticleukemia (CLL), chronic myelogenous leukemia (CML), diffuse large B-celllymphoma (DLBCL), mantle cell lymphoma, Non-Hodgkin lymphoma (includingrelapsed or refractory NHL and recurrent follicular), Hodgkin lymphoma,myeloproliferative diseases (e.g., primary myelofibrosis (PMF),polycythemia vera (PV), essential thrombocytosis (ET)), myelodysplasiasyndrome (MDS), and multiple myeloma.

Example sarcomas include, for example, chondrosarcoma, Ewing's sarcoma,osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma,myxoma, rhabdomyoma, fibroma, lipoma, harmatoma, and teratoma.

Example lung cancers include, for example, non-small cell lung cancer(NSCLC), bronchogenic carcinoma (squamous cell, undifferentiated smallcell, undifferentiated large cell, adenocarcinoma), alveolar(bronchiolar) carcinoma, bronchial adenoma, chondromatous hamartoma, andmesothelioma.

Example gastrointestinal cancers include, for example, cancers of theesophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma,lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas(ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoidtumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoidtumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma,fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma,hamartoma, leiomyoma), and colorectal cancer.

Example genitourinary tract cancers include, for example, cancers of thekidney (adenocarcinoma, Wilm's tumor [nephroblastoma]), bladder andurethra (squamous cell carcinoma, transitional cell carcinoma,adenocarcinoma), prostate (adenocarcinoma, sarcoma), and testis(seminoma, teratoma, embryonal carcinoma, teratocarcinoma,choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma,fibroadenoma, adenomatoid tumors, lipoma).

Example liver cancers include, for example, hepatoma (hepatocellularcarcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma,hepatocellular adenoma, and hemangioma.

Example bone cancers include, for example, osteogenic sarcoma(osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma,chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cellsarcoma), multiple myeloma, malignant giant cell tumor chordoma,osteochronfroma (osteocartilaginous exostoses), benign chondroma,chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant celltumors

Example nervous system cancers include, for example, cancers of theskull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans),meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma,meduoblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastomamultiform, oligodendroglioma, schwannoma, retinoblastoma, congenitaltumors), and spinal cord (neurofibroma, meningioma, glioma, sarcoma), aswell as neuroblastoma and Lhermitte-Duclos disease.

Example gynecological cancers include, for example, cancers of theuterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumorcervical dysplasia), ovaries (ovarian carcinoma (serouscystadenocarcinoma, mucinous cystadenocarcinoma, unclassifiedcarcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors,dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma,intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma),vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma(embryonal rhabdomyosarcoma), and fallopian tubes (carcinoma).

Example skin cancers include, for example, melanoma, basal cellcarcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplasticnevi, lipoma, angioma, dermatofibroma, and keloids.

The compounds and solid forms of the invention can further be used totreat cancer types where LSD1 may be overexpressed including, forexample, breast, prostate, head and neck, laryngeal, oral, and thyroidcancers (e.g., papillary thyroid carcinoma).

The compounds and solid forms of the invention can further be used totreat genetic disorders such as Cowden syndrome and Bannayan-Zonanasyndrome.

The compounds and solid forms of the invention can further be used totreat viral diseases such as herpes simplex virus (HSV), varicellazoster virus (VZV), human cytomegalovirus, hepatitis B virus (HBV), andadenovirus.

The compounds and solid forms of the invention can further be used totreat beta-globinopathies including, for example, beta-thalassemia andsickle cell anemia.

The term “contacting” as used in the context of in vitro and in vivosystem, refers to the bringing together of indicated moieties in an invitro system or an in vivo system. For example, “contacting” a LSD1protein with a compound of the invention includes the administration ofa compound of the present invention to an individual or patient, such asa human, having a LSD1 protein, as well as, for example, introducing acompound of the invention into a sample containing a cellular orpurified preparation containing the LSD1 protein.

As used herein, the term “individual” or “patient, ” usedinterchangeably, refers to any animal, including mammals, preferablymice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep,horses, or primates, and most preferably humans.

As used herein, the phrase “therapeutically effective amount” refers tothe amount of active compound or pharmaceutical agent that elicits thebiological or medicinal response that is being sought in a tissue,system, animal, individual or human by a researcher, veterinarian,medical doctor or other clinician.

The term “treating” or “treatment” as used in the context of treatingdiseases, condition or disorders refers to inhibiting the disease; forexample, inhibiting a disease, condition or disorder in an individualwho is experiencing or displaying the pathology or symptomatology of thedisease, condition or disorder (i.e., arresting further development ofthe pathology and/or symptomatology) or ameliorating the disease; forexample, ameliorating a disease, condition or disorder in an individualwho is experiencing or displaying the pathology or symptomatology of thedisease, condition or disorder (i.e., reversing the pathology and/orsymptomatology) such as decreasing the severity of disease.

As used herein, the term “preventing” or “prevention” refers topreventing the disease; for example, preventing a disease, condition ordisorder in an individual who may be predisposed to the disease,condition or disorder but does not yet experience or display thepathology or symptomatology of the disease.

Combination Therapies

The compounds and solid forms of the invention can be used incombination treatments where the compound of the invention isadministered in conjunction with other treatments such as theadministration of one or more additional therapeutic agents. Theadditional therapeutic agents are typically those which are normallyused to treat the particular condition to be treated. The additionaltherapeutic agents can include, e.g., chemotherapeutics,anti-inflammatory agents, steroids, immunosuppressants, as well asBcr-Abl, Flt-3, RAF, FAK, JAK, PIM, PI3K inhibitors for treatment ofLSD1-mediated diseases, disorders or conditions. The one or moreadditional pharmaceutical agents can be administered to a patientsimultaneously or sequentially.

In some embodiments, the compounds and solid forms of the invention canbe used in combination with a therapeutic agent that targets anepigenetic regulator. Examples of epigenetic regulators includebromodomain inhibitors, the histone lysine methyltransferases, histonearginine methyl transferases, histone demethylases, histonedeacetylases, histone acetylases, and DNA methyltransferases. Histonedeacetylase inhibitors include, e.g., vorinostat.

The compounds and solid forms described herein can be used incombination with one or more other kinase inhibitors for the treatmentof diseases, such as cancer, that are impacted by multiple signalingpathways. For example, a combination can include one or more inhibitorsof the following kinases for the treatment of cancer: Akt1, Akt2, Akt3,TGF-βR, Pim, PKA, PKG, PKC, CaM-kinase, phosphorylase kinase, MEKK, ERK,MAPK, mTOR, EGFR, HER2, HER3, HER4, INS-R, IGF-1R, IR-R, PDGFαR, PDGFβR,CSFIR, KIT, FLK-II, KDR/FLK-1, FLK-4, flt-1, FGFR1, FGFR2, FGFR3, FGFR4,c-Met, Ron, Sea, TRKA, TRKB, TRKC, FLT3, VEGFR/Flt2, Flt4, EphA1, EphA2,EphA3, EphB2, EphB4, Tie2, Src, Fyn, Lck, Fgr, Btk, Fak, SYK, FRK, JAK,ABL, ALK and B-Raf. Additionally, the compounds as described herein canbe combined with inhibitors of kinases associated with the PIK3/Akt/mTORsignaling pathway, such as PI3K, Akt (including Akt1, Akt2 and Akt3) andmTOR kinases.

The compounds and solid forms as described herein can be used incombination with one or more inhibitors of the enzyme or proteinreceptors such as HPK1, SBLB, TUT4, A2A/A2B, CD47, CDK2, STING, ALK2,LIN28, ADAR1, MAT2a, RIOK1, HDAC8, WDR5, SMARCA2, and DCLK1 for thetreatment of diseases and disorders. Exemplary diseases and disordersinclude cancer, infection, inflammation and neurodegenerative disorders.

One or more of the following agents may be used in combination with thecompounds and solid forms of the present disclosure and are presented asa non-limiting list: a cytostatic agent, taxotere, taxol, camptostar,epothilones, 5-fluorouracil, SCH 66336, R115777, L778,123, BMS 214662,IRESSA™ (gefitinib), TARCEVA™ (erlotinib), antibodies to EGFR, GLEEVEC™(imatinib mesylate), intron, ara-C, adriamycin, cytoxan, chlormethine,triethylenemelamine, triethylenethiophosphoramine, busulfan,6-mercaptopurine, 6-thioguanine, fludarabine phosphate, ELOXATIN™(oxaliplatin), vindesine, mithramycin, deoxycoformycin, L-asparaginase,17 alpha-ethinylestradiol, diethylstilbestrol, testosterone, prednisone,fluoxymesterone, methylprednisolone, methyltestosterone, prednisolone,triamcinolone, chlorotrianisene, hydroxyprogesterone, aminoglutethimide,medroxyprogesteroneacetate, leuprolide, flutamide, goserelin,hydroxyurea, amsacrine, navelbene, reloxafine, droloxafine,hexamethylmelamine, avastin, HERCEPTIN™ (trastuzumab), BEXXAR™(tositumomab), VELCADE™ (bortezomib), ZEVALIN™ (ibritumomab tiuxetan),TRISENOX™ (arsenic trioxide), XELODA™ (capecitabine), vinorelbine,porfimer, ERBITUX™ (cetuximab), aphidicolon, rituxan, Sml1, triapine,didox, trimidox, amidox, 3-AP, and MDL-101, 731.

For treating cancer and other proliferative diseases, the compounds andsolid forms of the invention can be used in combination withchemotherapeutic agents, or other anti-proliferative agents. Thecompounds of the invention can also be used in combination with medicaltherapy such as surgery or radiotherapy, e.g., gamma-radiation, neutronbeam radiotherapy, electron beam radiotherapy, proton therapy,brachytherapy, and systemic radioactive isotopes. Examples of suitablechemotherapeutic agents include any of: abarelix, aldesleukin,alemtuzumab, alitretinoin, allopurinol, altretamine, anastrozole,arsenic trioxide, asparaginase, azacitidine, baricitinib, bendamustine,bevacizumab, bexarotene, bleomycin, bortezombi, bortezomib, busulfanintravenous, busulfan oral, calusterone, capecitabine, carboplatin,carmustine, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine,cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dalteparinsodium, dasatinib, daunorubicin, decitabine, denileukin, denileukindiftitox, dexrazoxane, docetaxel, doxorubicin, dromostanolonepropionate, eculizumab, epirubicin, erlotinib, estramustine, etoposidephosphate, etoposide, exemestane, fentanyl citrate, filgrastim,floxuridine, fludarabine, fluorouracil, fulvestrant, gefitinib,gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelinacetate, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinibmesylate, interferon alfa 2a, irinotecan, lapatinib ditosylate,lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole,lomustine, meclorethamine, megestrol acetate, melphalan, mercaptopurine,methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone,nandrolone phenpropionate, nelarabine, niraparib, nofetumomab, olaparib,oxaliplatin, paclitaxel, pamidronate, panobinostat, panitumumab,pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin,pipobroman, plicamycin, procarbazine, quinacrine, rasburicase,rituximab, rucaparib, ruxolitinib, sorafenib, streptozocin, sunitinib,sunitinib maleate, tamoxifen, temozolomide, teniposide, testolactone,thalidomide, thioguanine, thiotepa, topotecan, toremifene, tositumomab,trastuzumab, tretinoin, uracil mustard, valrubicin, vinblastine,vincristine, vinorelbine, vorinostat, veliparib, talazoparib, andzoledronate.

For treating cancer and other proliferative diseases, the compounds andsolid forms of the invention can be used in combination withruxolitinib.

Additional examples of chemotherapeutics include proteosome inhibitors(e.g., bortezomib), thalidomide, revlimid, and DNA-damaging agents suchas melphalan, doxorubicin, cyclophosphamide, vincristine, etoposide,carmustine, and the like.

Example Bcr-Abl inhibitors include the compounds, and pharmaceuticallyacceptable salts.

Example suitable Flt-3 inhibitors include compounds, and theirpharmaceutically acceptable salts.

Example suitable RAF inhibitors include compounds, and theirpharmaceutically acceptable salts.

Example suitable FAK inhibitors include compounds, and theirpharmaceutically acceptable salts.

In some embodiments, the compounds and solid forms of the disclosure canbe used in combination with one or more other kinase inhibitorsincluding imatinib, particularly for treating patients resistant toimatinib or other kinase inhibitors.

The compounds and solid forms can be used in combination with tumorvaccines and CAR (Chimeric antigen receptor) T cell treatment as abooster for T cell activation (21). In some embodiments, tumor vaccinesinclude the proteins from viruses implicated in human cancers such asHuman Papilloma Viruses (HPV), Hepatitis Viruses (HBV and HCV) andKaposi's Herpes Sarcoma Virus (KHSV). In some embodiments, the compoundsand solid forms of the present disclosure can be used in combinationwith tumor specific antigen such as heat shock proteins isolated fromtumor tissue itself In some embodiments, the compounds and solid formscan be combined with dendritic cells immunization to activate potentanti-tumor responses.

Methods for the safe and effective administration of most of thesechemotherapeutic agents are known to those skilled in the art. Inaddition, their administration is described in the standard literature.For example, the administration of many of the chemotherapeutic agentsis described in the “Physicians' Desk Reference” (PDR, e.g., 1996edition, Medical Economics Company, Montvale, N.J.), the disclosure ofwhich is incorporated herein by reference as if set forth in itsentirety.

For treating cancer and other proliferative diseases, the compounds andsolid forms of the invention can be used in combination with targetedtherapies, including JAK kinase inhibitors (Ruxolitinib, additionalJAK1/2 and JAK1-selective, baricitinib or INCB39110), Pim kinaseinhibitors (e.g., INCB53914), PI3 kinase inhibitors including PI3K-deltaselective and broad spectrum PI3K inhibitors (e.g., INCB50465 andINCB54707), PI3K-gamma inhibitors such as PI3K-gamma selectiveinhibitors, MEK inhibitors, CSF1R inhibitors, TAM receptor tyrosinekinases inhibitors (Tyro-3, Axl, and Mer; e.g., INCB81776), angiogenesisinhibitors, interleukin receptor inhibitors, Cyclin Dependent kinaseinhibitors, BRAF inhibitors, mTOR inhibitors, proteasome inhibitors(Bortezomib, Carfilzomib), HDAC-inhibitors (panobinostat, vorinostat),DNA methyl transferase inhibitors, dexamethasone, bromo and extraterminal family members inhibitors (for example, bromodomain inhibitorsor BET inhibitors INCB54329 or INCB57643), LSD1 inhibitors (INCB59872),arginase inhibitors (INCB1158), indoleamine 2,3-dioxygenase inhibitors(epacadostat, NLG919 or BMS-986205), and PARP inhibitors (e.g., olaparibor rucaparib).

For treating autoimmune or inflammatory conditions, the compounds andsolid forms of the invention can be administered in combination with acorticosteroid such as triamcinolone, dexamethasone, fluocinolone,cortisone, prednisolone, or flumetholone.

For treating autoimmune or inflammatory conditions, the compounds andsolid forms of the invention can be administered in combination with animmune suppressant such as fluocinolone acetonide (Retisert®),rimexolone (AL-2178, Vexol, Alcon), or cyclosporine (Restasis®).

For treating autoimmune or inflammatory conditions, the compounds andsolid forms of the invention can be administered in combination with oneor more additional agents selected from Dehydrex™ (Holles Labs),Civamide (Opko), sodium hyaluronate (Vismed, Lantibio/TRB Chemedia),cyclosporine (ST-603, Sirion Therapeutics), ARG101(T) (testosterone,Argentis), AGR1012(P) (Argentis), ecabet sodium (Senju-Ista), gefarnate(Santen), 15-(s)-hydroxyeicosatetraenoic acid (15(S)-HETE), cevilemine,doxycycline (ALTY-0501, Alacrity), minocycline, iDestrin™ (NP50301,Nascent Pharmaceuticals), cyclosporine A (Nova22007, Novagali),oxytetracycline (Duramycin, MOLI1901, Lantibio), CF101(2S,3S,4R,5R)-3,4-dihydroxy-5-[6-[(3-iodophenyl)methylamino]purin-9-yl]-N-methyl-oxolane-2-carbamyl,Can-Fite Biopharma), voclosporin (LX212 or LX214, Lux Biosciences),ARG103 (Agentis), RX-10045 (synthetic resolvin analog, Resolvyx), DYN15(Dyanmis Therapeutics), rivoglitazone (DE011, Daiichi Sanko), TB4(RegeneRx), OPH-01 (Ophtalmis Monaco), PCS101 (Pericor Science), REV1-31(Evolutec), Lacritin (Senju), rebamipide (Otsuka-Novartis), OT-551(Othera), PAI-2 (University of Pennsylvania and Temple University),pilocarpine, tacrolimus, pimecrolimus (AMS981, Novartis), loteprednoletabonate, rituximab, diquafosol tetrasodium (INS365, Inspire), KLS-0611(Kissei Pharmaceuticals), dehydroepiandrosterone, anakinra, efalizumab,mycophenolate sodium, etanercept (Embrel®), hydroxychloroquine, NGX267(TorreyPines Therapeutics), or thalidomide.

In some embodiments, the compounds and solid forms of the invention canbe administered in combination with one or more agents selected from anantibiotic, antiviral, antifungal, anesthetic, anti-inflammatory agentsincluding steroidal and non-steroidal anti-inflammatories, andanti-allergic agents. Examples of suitable medicaments includeaminoglycosides such as amikacin, gentamycin, tobramycin, streptomycin,netilmycin, and kanamycin; fluoroquinolones such as ciprofloxacin,norfloxacin, ofloxacin, trovafloxacin, lomefloxacin, levofloxacin, andenoxacin; naphthyridine; sulfonamides; polymyxin; chloramphenicol;neomycin; paramomycin; colistimethate; bacitracin; vancomycin;tetracyclines; rifampin and its derivatives (“rifampins”); cycloserine;beta-lactams; cephalosporins; amphotericins; fluconazole; flucytosine;natamycin; miconazole; ketoconazole; corticosteroids; diclofenac;flurbiprofen; ketorolac; suprofen; cromolyn; lodoxamide; levocabastin;naphazoline; antazoline; pheniramine; or azalide antibiotic.

Other examples of agents, one or more of which a provided compound orsolid form may also be combined with include: a treatment forAlzheimer's Disease such as donepezil and rivastigmine; a treatment forParkinson's Disease such as L-DOPA/carbidopa, entacapone, ropinirole,pramipexole, bromocriptine, pergolide, trihexyphenidyl, and amantadine;an agent for treating multiple sclerosis (MS) such as beta interferon(e.g., Avonex® and Rebif®), glatiramer acetate, and mitoxantrone; atreatment for asthma such as albuterol and montelukast; an agent fortreating schizophrenia such as zyprexa, risperdal, seroquel, andhaloperidol; an anti-inflammatory agent such as a corticosteroid, suchas dexamethasone or prednisone, a TNF blocker, IL-1 RA, azathioprine,cyclophosphamide, and sulfasalazine; an immunomodulatory agent,including immunosuppressive agents, such as cyclosporin, tacrolimus,rapamycin, mycophenolate mofetil, an interferon, a corticosteroid,cyclophosphamide, azathioprine, and sulfasalazine; a neurotrophic factorsuch as an acetylcholinesterase inhibitor, an MAO inhibitor, aninterferon, an anti-convulsant, an ion channel blocker, riluzole, or ananti-Parkinson's agent; an agent for treating cardiovascular diseasesuch as a beta-blocker, an ACE inhibitor, a diuretic, a nitrate, acalcium channel blocker, or a statin; an agent for treating liverdisease such as a corticosteroid, cholestyramine, an interferon, and ananti-viral agent; an agent for treating blood disorders such as acorticosteroid, an anti-leukemic agent, or a growth factor; or an agentfor treating immunodeficiency disorders such as gamma globulin.

Biological drugs, such as antibodies and cytokines, used as anticancerangents, can be combined with the compounds of the invention. Inaddition, drugs modulating microenvironment or immune responses can becombined with the compounds of the invention. Examples of such drugs areanti-Her2 antibodies, anti-CD20 antibodies, anti-CTLA1, anti-PD-1,anti-PDL1, and other immunotherapeutic drugs.

Example antibodies for use in combination therapy include but are notlimited to Trastuzumab (e.g. anti-HER2), Ranibizumab (e.g. anti-VEGF-A),Bevacizumab (trade name Avastin, e.g. anti-VEGF, Panitumumab (e.g.anti-EGFR), Cetuximab (e.g. anti-EGFR), Rituxan (anti-CD20) andantibodies directed to c-MET.

Formulation, Dosage Forms and Administration

When employed as pharmaceuticals, the compounds and solid forms of theinvention can be administered in the form of pharmaceuticalcompositions. These compositions can be prepared in a manner well knownin the pharmaceutical art, and can be administered by a variety ofroutes, depending upon whether local or systemic treatment is desiredand upon the area to be treated. Administration may be topical(including transdermal, epidermal, ophthalmic and to mucous membranesincluding intranasal, vaginal and rectal delivery), pulmonary (e.g., byinhalation or insufflation of powders or aerosols, including bynebulizer; intratracheal or intranasal), oral or parenteral. Parenteraladministration includes intravenous, intraarterial, subcutaneous,intraperitoneal intramuscular or injection or infusion; or intracranial,e.g., intrathecal or intraventricular, administration. Parenteraladministration can be in the form of a single bolus dose, or may be, forexample, by a continuous perfusion pump. Pharmaceutical compositions andformulations for topical administration may include transdermal patches,ointments, lotions, creams, gels, drops, suppositories, sprays, liquidsand powders. Conventional pharmaceutical carriers, aqueous, powder oroily bases, thickeners and the like may be necessary or desirable.

This invention also includes pharmaceutical compositions which contain,as the active ingredient, the compound and solid forms of the inventionor a pharmaceutically acceptable salt thereof, in combination with oneor more pharmaceutically acceptable carriers (excipients). In someembodiments, the composition is suitable for topical administration. Inmaking the compositions of the invention, the active ingredient istypically mixed with an excipient, diluted by an excipient or enclosedwithin such a carrier in the form of, for example, a capsule, sachet,paper, or other container. When the excipient serves as a diluent, itcan be a solid, semi-solid, or liquid material, which acts as a vehicle,carrier or medium for the active ingredient. Thus, the compositions canbe in the form of tablets, pills, powders, lozenges, sachets, cachets,elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solidor in a liquid medium), ointments containing, for example, up to 10% byweight of the active compound, soft and hard gelatin capsules,suppositories, sterile injectable solutions, and sterile packagedpowders.

In preparing a formulation, the active compound or solid form can bemilled to provide the appropriate particle size prior to combining withthe other ingredients. If the active compound or solid form issubstantially insoluble, it can be milled to a particle size of lessthan 200 mesh. If the active compound or solid form is substantiallywater soluble, the particle size can be adjusted by milling to provide asubstantially uniform distribution in the formulation, e.g., about 40mesh.

The compounds and solid forms of the invention may be milled using knownmilling procedures such as wet milling to obtain a particle sizeappropriate for tablet formation and for other formulation types. Finelydivided (nanoparticulate) preparations of the compounds and solid formsof the invention can be prepared by processes known in the art, e.g.,see International App. No. WO 2002/000196.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate, and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions of the invention can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

The compositions can be formulated in a unit dosage form, each dosagecontaining from about 5 to about 1,000 mg (1 g), more usually about 100mg to about 500 mg, of the active ingredient. The term “unit dosageforms” refers to physically discrete units suitable as unitary dosagesfor human subjects and other mammals, each unit containing apredetermined quantity of active material calculated to produce thedesired therapeutic effect, in association with a suitablepharmaceutical excipient.

The active compound may be effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount. It willbe understood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound or solid form of the present invention. When referring to thesepreformulation compositions as homogeneous, the active ingredient istypically dispersed evenly throughout the composition so that thecomposition can be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid preformulation isthen subdivided into unit dosage forms of the type described abovecontaining from, for example, about 0.1 to about 1000 mg of the activeingredient of the present invention.

The tablets or pills of the present invention can be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permit theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol, and cellulose acetate.

The liquid forms in which the compounds and compositions of the presentinvention can be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect.Compositions can be nebulized by use of inert gases. Nebulized solutionsmay be breathed directly from the nebulizing device or the nebulizingdevice can be attached to a face masks tent, or intermittent positivepressure breathing machine. Solution, suspension, or powder compositionscan be administered orally or nasally from devices which deliver theformulation in an appropriate manner.

Topical formulations can contain one or more conventional carriers. Insome embodiments, ointments can contain water and one or morehydrophobic carriers selected from, for example, liquid paraffin,polyoxyethylene alkyl ether, propylene glycol, white vaseline, and thelike. Carrier compositions of creams can be based on water incombination with glycerol and one or more other components, e.g.,glycerinemonostearate, PEG-glycerinemonostearate and cetylstearylalcohol. Gels can be formulated using isopropyl alcohol and water,suitably in combination with other components such as, for example,glycerol, hydroxyethyl cellulose, and the like. In some embodiments,topical formulations contain at least about 0.1, at least about 0.25, atleast about 0.5, at least about 1, at least about 2, or at least about 5wt % of the compound or solid form of the invention. The topicalformulations can be suitably packaged in tubes of, for example, 100 gwhich are optionally associated with instructions for the treatment ofthe select indication, e.g., psoriasis or other skin condition.

The amount of compound or solid form or composition administered to apatient will vary depending upon what is being administered, the purposeof the administration, such as prophylaxis or therapy, the state of thepatient, the manner of administration, and the like. In therapeuticapplications, compositions can be administered to a patient alreadysuffering from a disease in an amount sufficient to cure or at leastpartially arrest the symptoms of the disease and its complications.Effective doses will depend on the disease condition being treated aswell as by the judgment of the attending clinician depending uponfactors such as the severity of the disease, the age, weight and generalcondition of the patient, and the like.

The compositions administered to a patient can be in the form ofpharmaceutical compositions described above. These compositions can besterilized by conventional sterilization techniques, or may be sterilefiltered. Aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterileaqueous carrier prior to administration. The pH of the compoundpreparations typically will be between 3 and 11, more preferably from 5to 9 and most preferably from 7 to 8. It will be understood that use ofcertain of the foregoing excipients, carriers, or stabilizers willresult in the formation of pharmaceutical salts.

The therapeutic dosage of a compound of the present invention can varyaccording to, for example, the particular use for which the treatment ismade, the manner of administration of the compound, the health andcondition of the patient, and the judgment of the prescribing physician.The proportion or concentration of a compound of the invention in apharmaceutical composition can vary depending upon a number of factorsincluding dosage, chemical characteristics (e.g., hydrophobicity), andthe route of administration. For example, the compounds of the inventioncan be provided in an aqueous physiological buffer solution containingabout 0.1 to about 10% w/v of the compound for parenteraladministration. Some typical dose ranges are from about 1 μg/kg to about1 g/kg of body weight per day. In some embodiments, the dose range isfrom about 0.01 mg/kg to about 100 mg/kg of body weight per day. Thedosage is likely to depend on such variables as the type and extent ofprogression of the disease or disorder, the overall health status of theparticular patient, the relative biological efficacy of the compoundselected, formulation of the excipient, and its route of administration.Effective doses can be extrapolated from dose-response curves derivedfrom in vitro or animal model test systems.

The compositions of the invention can further include one or moreadditional pharmaceutical agents such as a chemotherapeutic, steroid,anti-inflammatory compound, or immunosuppressant, examples of which arelisted hereinabove.

The compounds and solid forms of the invention can be provided with orused in combination with a companion diagnostic. As used herein, theterm “companion diagnostic” refers to a diagnostic device useful fordetermining the safe and effective use of a therapeutic agent. Forexample, a companion diagnostic may be used to customize dosage of atherapeutic agent for a given subject, identify appropriatesubpopulations for treatment, or identify populations who should notreceive a particular treatment because of an increased risk of a seriousside effect.

In some embodiments, the companion diagnostic is used to monitortreatment response in a patient. In some embodiments, the companiondiagnostic is used to identify a subject that is likely to benefit froma given compound or therapeutic agent. In some embodiments, thecompanion diagnostic is used to identify a subject having an increasedrisk of adverse side effects from administration of a therapeutic agent,compared to a reference standard. In some embodiments, the companiondiagnostic is an in vitro diagnostic or imaging tool selected from thelist of FDA cleared or approved companion diagnostic devices. In someembodiments, the companion diagnostic is selected from the list of teststhat have been cleared or approved by the Center for Devices andRadiological Health.

Labeled Compounds and Assay Methods

Another aspect of the present invention relates to labeled compounds ofthe invention (radio-labeled, fluorescent-labeled, etc.) that would beuseful not only in imaging techniques but also in assays, both in vitroand in vivo, for localizing and quantitating LSD1 in tissue samples,including human, and for identifying LSD1 ligands by inhibition bindingof a labeled compound. Substitution of one or more of the atoms of thecompounds of the present disclosure can also be useful in generatingdifferentiated ADME (Adsorption, Distribution, Metabolism andExcretion). Accordingly, the present invention includes LSD1 assays thatcontain such labeled or substituted compounds.

The present invention further includes isotopically-labeled compounds ofthe invention. An “isotopically” or “radio-labeled” compound is acompound of the invention where one or more atoms are replaced orsubstituted by an atom having an atomic mass or mass number differentfrom the atomic mass or mass number typically found in nature (i.e.,naturally occurring). Suitable radionuclides that may be incorporated incompounds of the present invention include but are not limited to ²H(also written as D for deuterium), ³H (also written as T for tritium)¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸F, ³⁵S, ³⁶Cl, ⁸²Br, ⁷⁵Br, ⁷⁶Br,⁷⁷B, ¹²³I, ¹²⁴I, ¹²⁵I and ¹³¹I. For example, one or more hydrogen atomsin a compound of the present invention can be replaced by deuteriumatoms (e.g., one or more hydrogen atoms of a C₁₋₆ alkyl group of acompound provided herein can be optionally substituted with deuteriumatoms, such as —CD₃ being substituted for —CH₃). In some embodiments,alkyl groups in Formula (I) can be perdeuterated.

One or more constituent atoms of the compounds presented herein can bereplaced or substituted with isotopes of the atoms in natural ornon-natural abundance. In some embodiments, the compound includes atleast one deuterium atom. In some embodiments, the compound includes twoor more deuterium atoms. In some embodiments, the compound includes 1-2,1-3, 1-4, 1-5, or 1-6 deuterium atoms. In some embodiments, all of thehydrogen atoms in a compound can be replaced or substituted by deuteriumatoms.

In some embodiments, 1, 2, 3, 4, 5, 6, 7, or 8 hydrogen atoms, attachedto carbon atoms of “alkyl”, “alkenyl”, “alkynyl”, “aryl”, “phenyl”,“cycloalkyl”, “heterocycloalkyl”, or “heteroaryl” substituents or “—C₁₋₆alkyl-”, “alkylene”, “alkenylene” and “alkynylene” linking groups, asdescribed herein, are optionally replaced by deuterium atoms.

Synthetic methods for including isotopes into organic compounds areknown in the art (Deuterium Labeling in Organic Chemistry by Alan F.Thomas (New York, N.Y., Appleton-Century-Crofts, 1971; The Renaissanceof H/D Exchange by Jens Atzrodt, Volker Derdau, Thorsten Fey and JochenZimmermann, Angew. Chem. Int. Ed. 2007, 7744-7765; The Organic Chemistryof Isotopic Labelling by James R. Hanson, Royal Society of Chemistry,2011). Isotopically labeled compounds can be used in various studiessuch as NMR spectroscopy, metabolism experiments, and/or assays.

Substitution with heavier isotopes, such as deuterium, may affordcertain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life or reduced dosagerequirements, and hence may be preferred in some circumstances. (seee.g., A. Kerekes et. al. J. Med. Chem. 2011, 54, 201-210; R. Xu et. al.J. Label Compd. Radiopharm. 2015, 58, 308-312). In particular,substitution at one or more metabolism sites may afford one or more ofthe therapeutic advantages.

The radionuclide that is incorporated in the instant radio-labeledcompounds will depend on the specific application of that radio-labeledcompound. For example, for in vitro LSD1 and competition assays,compounds that incorporate ³H, ¹⁴C, ⁸²Br, ¹²⁵I, ¹³¹I or ³⁵S can beuseful. For radio-imaging applications ¹¹C, ¹⁸F, ¹²⁵I, ¹²³I, ¹²⁴I, ¹³¹I,⁷⁵Br, ⁷⁶Br or ⁷⁷Br can be useful.

It is understood that a “radio-labeled ” or “labeled compound” is acompound that has incorporated at least one radionuclide. In someembodiments the radionuclide is selected from the group consisting of³H, ¹⁴C, ¹²⁵I, ³⁵S and ⁸²Br.

The present invention can further include synthetic methods forincorporating radio-isotopes into compounds of the invention. Syntheticmethods for incorporating radio-isotopes into organic compounds are wellknown in the art, and an ordinary skill in the art will readilyrecognize the methods applicable for the compounds of invention.

A labeled compound of the invention can be used in a screening assay toidentify/evaluate compounds. For example, a newly synthesized oridentified compound (i.e., test compound) which is labeled can beevaluated for its ability to bind LSD1 by monitoring its concentrationvariation when contacting with LSD1, through tracking of the labeling.For example, a test compound (labeled) can be evaluated for its abilityto reduce binding of another compound which is known to bind to LSD1(i.e., standard compound). Accordingly, the ability of a test compoundto compete with the standard compound for binding to LSD1directlycorrelates to its binding affinity. Conversely, in some other screeningassays, the standard compound is labeled and test compounds areunlabeled. Accordingly, the concentration of the labeled standardcompound is monitored in order to evaluate the competition between thestandard compound and the test compound, and the relative bindingaffinity of the test compound is thus ascertained.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of non-criticalparameters which can be changed or modified to yield essentially thesame results. The compounds of the Examples were found to be inhibitorsof LSD1 as described below.

EXAMPLES

Experimental procedures for compounds of the invention are providedbelow.

Preparatory LC-MS purifications of some of the compounds prepared wereperformed on Waters mass directed fractionation systems. The basicequipment setup, protocols, and control software for the operation ofthese systems have been described in detail in the literature. See e.g.“Two-Pump At Column Dilution Configuration for Preparative LC-MS”, K.Blom, J. Combi. Chem., 4, 295 (2002); “Optimizing Preparative LC-MSConfigurations and Methods for Parallel Synthesis Purification”, K.Blom, R. Sparks, J. Doughty, G. Everlof, T. Hague, A. Combs, J. Combi.Chem., 5, 670 (2003); and “Preparative LC-MS Purification: ImprovedCompound Specific Method Optimization”, K. Blom, B. Glass, R. Sparks, A.Combs, J. Combi. Chem., 6, 874-883 (2004). The compounds separated weretypically subjected to analytical liquid chromatography massspectrometry (LCMS) for purity check under the following conditions:Instrument; Agilent 1100 series, LC/MSD, Column: Waters Sunfire™ C₁₈ 5μm particle size, 2.1×5.0 mm, Buffers: mobile phase A: 0.025% TFA inwater and mobile phase B: acetonitrile; gradient 2% to 80% of B in 3minutes with flow rate 2.0 mL/minute.

The following abbreviations may be used herein: AcOH (acetic acid); Ac₂O(acetic anhydride); aq. (aqueous); atm. (atmosphere(s)); Boc(t-butoxycarbonyl); BOP((benzotriazol-1-yloxy)tris(dimethylamino)phosphoniumhexafluorophosphate); br (broad); Cbz (carboxybenzyl); calc.(calculated); d (doublet); dd (doublet of doublets); DBU(1,8-diazabicyclo[5.4.0]undec-7-ene); DCM (dichloromethane); DIAD(N,N′-diisopropyl azidodicarboxylate); DIEA (N,N-diisopropylethylamine);DIPEA (N,N-diisopropylethylamine); DIBAL (diisobutylaluminium hydride);DMF (N,N-dimethylformamide); Et (ethyl); EtOAc (ethyl acetate); FCC(flash column chromatography); g (gram(s)); h (hour(s)); HATU(N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate); HCl (hydrochloric acid); HPLC (high performanceliquid chromatography); Hz (hertz); J (coupling constant); LCMS (liquidchromatography-mass spectrometry); LDA (lithium diisopropylamide); m(multiplet); M (molar); mCPBA (3-chloroperoxybenzoic acid); MS (Massspectrometry); Me (methyl); MeCN (acetonitrile); MeOH (methanol); mg(milligram(s)); min. (minutes(s)); mL (milliliter(s)); mmol(millimole(s)); N (normal); nM (nanomolar); NMP (N-methylpyrrolidinone);NMR (nuclear magnetic resonance spectroscopy); OTf(trifluoromethanesulfonate); Ph (phenyl); pM (picomolar); RP-HPLC(reverse phase high performance liquid chromatography); r.t. (roomtemperature), s (singlet); t (triplet or tertiary); TBS(tert-butyldimethylsilyl); tert (tertiary); tt (triplet of triplets);TFA (trifluoroacetic acid); THF (tetrahydrofuran); μg (microgram(s));(microliter(s)); μM (micromolar); wt % (weight percent).

Intermediate 1. 3-(cyanomethylene)azetidine-1-sulfonamide

Step 1. 2-(Azetidin-3-ylidene)acetonitrile hydrochloride

To a solution of tert-butyl 3-(cyanomethylene) azetidine-1-carboxylate(150.0 g, 772 mmol) in dichloromethane (1.48 L) was added a 5.25 Msolution of HCl in isopropyl alcohol (1.47 L, 7723 mmol) with anaddition funnel. After the reaction mixture was stirred at roomtemperature for 4 h, heptane (3.0 L) was added. The mixture was stirredfor 1 hour, filtered and dried by pulling air through the resulting caketo give 89.5 g of the title compound (yield: 89%, white solid). ¹H NMR(400 MHz, DMSO) δ 9.96 (s, 2H), 6.25-5.66 (m, 1H), 5.13-4.47 (m, 4H).

Step 2. Tert-butyl ((3-(cyanomethylene)azetidin-1-yl)sulfonyl)carbamate

A solution of tert-butyl alcohol (123 g, 1660 mmol) in dichloromethane(660 mL, 6V) was allowed to stir and cooled via a salt/ice bath. To thissolution, sulfurisocyanatidic chloride (128 mL, 1468 mmol) dissolved indichloromethane (660 mL, 6V) was added slowly via addition funnel, asthe temperature of the solution was held from 1.2° C. to 5.5° C.). Thesolution was stirred for 1 h at 3° C., providing a solution oftert-butyl chlorosulfonylcarbamate.

To a suspension of 2-(azetidin-3-ylidene) acetonitrile hydrochloride(Step 1, 166.7 g, 1277 mmol) in dichloromethane (1660 mL, 10V) was addedtriethylamine (445 mL, 3192 mmol). After stirring for 30 minutes, thereaction mixture was cooled down to 0° C. To this mixture was slowlyadded the prepared solution of tert-butyl chlorosulfonylcarbamate withan addition funnel, holding the temperature between 2 and 13° C. Thereaction mixture was then stirred at 0° C. for 1 h. The reaction mixturewas diluted with dichloromethane (300 mL). The reaction mixture waspartitioned between dichloromethane and 0.2N HCl in water (3.55 L). Theorganics were dried over MgSO₄ and concentrated to give the titlecompound (352 g, 101%). LC-MS calculated for C₁₀H₁₅N₃O₄S [M+H]⁺ m/z:274.0; found 296.0 (M+Na). ¹H NMR (400 MHz, CDCl₃) δ 7.14 (s, 1H), 5.46(s, 1H), 3.74 (s, 2H), 3.24 (s, 2H), 1.56 (s, 9H).

Step 3. 3-(Cyanomethylene) azetidine-1-sulfonamide (Intermediate 1)

To a solution of tert-butyl((3-(cyanomethylene)azetidin-1-yl)sulfonyl)carbamate (Step 2, 349 g,1277 mmol) in dichloromethane (3.85 L) was added trifluoroacetic acid(582 g, 394 mL, 5108 mmol) via an addition funnel at room temperature.The reaction mixture was stirred at 30-38° C. (internal) for 3 h. Thereaction mixture was concentrated to remove dichloromethane, and thendissolved in EtOAc (2.0 L). To the solution was added 7% NaHCO₃/watersolution to reach pH 8. The aqueous layer was extracted with EtOAc (800mL each) twice and the organic layers were combined, dried andconcentrated to give crude 3-(cyanomethylene) azetidine-1-sulfonamide(203.4 g, 92%).

The crude product was dissolved in EtOAc (6V) and MeOH (1V) at 55° C.(oil bath temperature). Heptane was added (10V) at 55° C., and thesolution became cloudy. The mixture was stirred at room temperature for5 h. Filtration gave the desired product. LC-MS calculated for C₅H₇N₃O₂S[M+H]⁺ m/z: 174.0; found 174.0 (weak ionization). ¹H NMR (400 MHz, MeOD)δ 5.69 (s, 1H), 4.76-4.41 (m, 4H).

Example 1 Synthesis of3-(cyanomethyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamide(Compound 1)

Step 1. 1-(2,2,2-Trifluoroacetyl)piperidin-4-one (7)

To a suspension of piperidin-4-one hydrochloride hydrate (248 g, 1615mmol) in dichloromethane (2.48 L, 10V) was added triethylamine (248 ml,1776 mmol) at 0° C. The mixture was stirred for 5 min, then2,2,2-trifluoroacetic anhydride (471 ml, 3390 mmol) in dichloromethane(940 mL) was added via addition funnel (over 1 h) at 0° C. Afteraddition was complete, the cooling bath was removed and the reactionmixture was warmed to room temperature. After 2.5 h, the reaction wascomplete. The reaction mixture was poured into 900 mL of 0.2 M HCl inwater. The reaction mixture was partitioned between dichloromethane andwater. After separation, the water layer was back extracted withdichloromethane (600 mL). The combined organic layers were washed with 1L water, twice, then 1 L brine. The organic phase was dried with 150 gmagnesium sulfate, filtered, and concentrated. The resulting solid wasdried under high vacuum. 1-(2,2,2-trifluoroacetyl)piperidin-4-one (303g, 1615 mmol) was obtained as a solid in 96% yield. LC-MS calculated forC₇H₈F₃NO₂ [M+H]⁺ m/z: 196.0; found 196.0. ¹H NMR (400 MHz, CDCl₃) δ4.06-3.77 (dt, J=23.1, 6.4 Hz, 4H), 2.76-2.46 (q, J=6.6 Hz, 4H).

Step 2.Tert-butyl((1R,2S)-2-phenylcyclopropyl)(1-(2,2,2-trifluoroacetyl)piperidin-4-yl)carbamate(5)

1-(2,2,2-Trifluoroacetyl)piperidin-4-one (24.96 g, 128 mmol) and(1R,2S)-2-phenylcyclopropan-1-amine (19.94 g, 141 mmol) were dissolvedin dichloromethane (340 ml). Acetic acid (15.38 ml, 269 mmol) was addedand the reaction mixture was stirred at room temperature for 1 h. Thereaction mixture was then cooled to 0° C. Sodium triacetoxyhydroborate(32.5 g, 153 mmol) was added in six 5.4 g portions over 30 minutes. Thereaction mixture was stirred at 0° C. for 4 h, until the reaction wascomplete. 7% NaHCO₃ in water (200 mL) was added. The mixture was stirredfor 30 min, after which time the organic and aqueous phases wereseparated. The organic phase was dried with sodium sulfate, filtered,and returned to a 1 L round bottom flask. Di-tert-butyl dicarbonate(30.7 g, 141 mmol) was added, and the reaction mixture was heated to 38°C. The reaction mixture was stirred at 38° C. until complete. Thereaction mixture was then cooled to room temperature, and water (200 mL)was added. The organic and aqueous phases were separated. The organicphase was dried with sodium sulfate, filtered, and concentrated toprovide 50.8 g of oil that was used as is in the subsequent step. LC-MScalculated for C₂₁H₂₇F₃N₂O₃ [M+H]⁺ m/z: 413.2; found 413.2. ¹H NMR (400MHz, CDCl₃) δ 7.34-7.26 (m, 2H), 7.26-7.16 (m, 1H), 7.12-7.05 (m, 2H),4.71-4.60 (m, 1H), 4.16-4.02 (td, J=15.4, 12.9, 4.1 Hz, 1H), 4.01-3.88(tt, J=11.9, 4.1 Hz, 1H), 3.20-3.08 (m, 1H), 2.83-2.70 (tt, J=13.3, 3.6Hz, 1H), 2.63-2.53 (dtd, J=8.0, 4.5, 3.3 Hz, 1H), 2.20-1.85 (m, 5H),1.49-1.42 (d, J=1.6 Hz, 9H), 1.40-1.22 (m, 2H).

Step 3. Tert-butyl((1S,2S)-2-phenylcyclopropyl)(piperidin-4-yl)carbamate(3)

In a 1 L flask, tert-butyl((1R,2S)-2-phenylcyclopropyl)(1-(2,2,2-trifluoroacetyl)piperidin-4-yl)carbamate(50.8 g, 118 mmol) was dissolved in methanol (500 ml). Potassiumhydroxide (19.78 g, 353 mmol) in water (20 ml) was added slowly. Thereaction mixture was heated to 55° C. and stirred for 2 h, at which timethe starting material was consumed and the reaction mixture was cooledto room temperature. The methanol was removed via rotavap. The cruderesidue was dissolved in MTBE (500 mL) and washed with 250 mL water. Theaqueous layer was back extracted by MTBE (500 mL). The organic phase wasdried and the solvent was removed under reduced pressure to give 34.5 gof crude product.

To the product tert-butyl((1R,2S)-2-phenylcyclopropyl)(piperidin-4-yl)carbamate (34.5 g, 109mmol) in 2-propanol (415 ml, 12 V) was added a solution of L-Tartaricacid (18.00 g, 120 mmol) in MeOH (25 ml, 1.5 V). The mixture was stirredat room temperature for 14 h, after which time heptane (520 mL, 15 V)was added. The slurry was stirred for 2 h, after which time the whitesolid was collected by filtration and dried to afford tert-butyl((1S,2S)-2-phenylcyclopropyl)(piperidin-4-yl) carbamate Tartrate (40 g,85 mmol) in 78% yield.

To a suspension of tert-butyl((1R,2S)-2-phenylcyclopropyl)(piperidin-4-yl) carbamate Tartrate (30 g,64.2 mmol) in MTBE (300 mL, 10V) was added sodium bicarbonate (17.27 g,206 mmol) as a solution in 300 mL water (10V). The reaction mixture wasstirred for 1 h, then partitioned between MTBE and water. The organiclayer was separated and washed with additional saturated NaHCO₃ (100mL). The organic phase was separated, dried with sodium sulfate, andfiltered into a round bottom flask. MTBE was removed under reducedpressure to afford tert-butyl((1R,2S)-2-phenylcyclopropyl)(piperidin-4-yl) carbamate (19.2 g, 60.6mmol) in 94% yield. LC-MS calculated for C₁₉H₂₈N₂O₂ [M+H]⁺ m/z: 317.2;found 317.2. ¹H NMR (600 MHz, MeOD) δ 7.31-7.22 (m, 2H), 7.21-7.10 (m,3H), 3.82-3.73 (tt, J=12.1, 3.7 Hz, 1H), 3.15-3.05 (dddt, J=23.7, 12.5,4.1, 2.0 Hz, 2H), 2.67-2.58 (m, 3H), 2.19-2.10 (ddd, J=9.9, 6.5, 3.5 Hz,1H), 2.08-1.99 (m, 1H), 1.94-1.86 (m, 1H), 1.84-1.77 (ddt, J=15.0, 4.8,2.4 Hz, 1H), 1.79-1.71 (m, 1H), 1.48 (s, 10H), 1.30-1.21 (dt, J=7.3, 6.1Hz, 1H).

Step 4:Tert-butyl(1-(3-(cyanomethyl)-1-sulfamoylazetidin-3-yl)piperidin-4-yl)((1R,2S)-2-phenylcyclopropyl)carbamate(2)

tert-butyl ((1R,2S)-2-phenylcyclopropyl)(piperidin-4-yl)carbamate (11.6g, 36.7 mmol) and 3-(cyanomethylene) azetidine-1-sulfonamide(Intermediate 1, 7.30 g, 42.2 mmol) were dissolved in methanol (30 ml, 4V). The reaction mixture was heated to 60° C. and stirred for 8 h, afterwhich time the reaction was judged complete by HPLC. The reactionmixture was cooled to room temperature. Water (60.0 ml, 8 V) was addeddropwise. After a milky solution formed, addition was stopped, and themixture was stirred for 5 min until a beige solid was observed. Theremaining water was added. The mixture was stirred at room temperaturefor 14 h. The solid was isolated via filtration and washed with water(60 mL). The solid was dried to a constant weight. The solid was thendissolved in methanol (80 mL) at 45° C. The solution was cooled to roomtemperature, at which time precipitate formed. Water (70 mL) was addeddropwise while stirring at room temperature. The mixture was stirred for1 h after addition. The solid was isolated via filtration and dried toafford tert-butyl(1-(3-(cyanomethyl)-1-sulfamoylazetidin-3-yl)piperidin-4-yl)((1R,2S)-2-phenylcyclopropyl)carbamate(17 g, 34.5 mmol) in 94% yield. LC-MS calculated for C₂₄H₃₅N₅O₄S [M+H]⁺m/z: 490.2; found 490.1. ¹H NMR (500 MHz, MeOD) δ 7.31-7.24 (m, 2H),7.21-7.10 (m, 3H), 3.83-3.76 (dd, J=8.0, 6.9 Hz, 2H), 3.69-3.59 (m, 3H),3.02 (s, 2H), 2.88-2.76 (m, 2H), 2.66-2.59 (ddd, J=7.8, 4.6, 3.5 Hz,1H), 2.41-2.31 (tdd, J=11.5, 4.6, 2.4 Hz, 2H), 2.19-2.08 (m, 2H),2.05-1.94 (m, 1H), 1.86-1.73 (dddd, J=25.5, 12.1, 4.3, 2.5 Hz, 2H), 1.46(s, 10H), 1.29-1.21 (dt, J=7.3, 6.2 Hz, 1H).

Step 5.3-(Cyanomethyl)-3-(4-{[(1R,2S)-2-phenylcyclopropy]amino}piperidin-1-yl)azetidine-1-sulfonamidedihydrochloride (1)

Tert-butyl(1-(3-(cyanomethyl)-1-sulfamoylazetidin-3-yl)piperidin-4-yl)((1R,2S)-2-phenylcyclopropyl)carbamate (2.0 g, 4.08 mmol) was dissolved in methanol (6 mL, 3 V) andmethanolic HCl (3.0 M, 12.0 mL). The reaction mixture was heated to 40°C. and stirred for 3 h, at which time the reaction was judged completeby HPLC. After cooling to room temperature, a white precipitate formed.MTBE (36 mL, 18 V) was added and the mixture was stirred at roomtemperature. Filtration provided the desired product (1.7 g) in 90%yield. LC-MS calculated for C₁₉H₂₉Cl₂N₅O₂S [M+H]⁺ m/z: 390.1; found390.1. ¹H NMR (400 MHz, D₂O) δ 7.43-7.27 (m, 3H), 7.25-7.17 (m, 2H),4.20-4.13 (d, J=9.8 Hz, 2H), 4.09-4.01 (d, J=9.8 Hz, 2H), 3.71-3.58 (tt,J=11.9, 4.2 Hz, 1H), 3.48-3.33 (m, 4H), 3.12-2.95 (dddt, J=23.8, 11.8,8.0, 3.4 Hz, 3H), 2.59-2.39 (m, 3H), 2.08-1.96 (m, 2H), 1.60-1.43 (m,2H).

Example 2 Alternative Preparation of3-(cyanomethyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamide(Compound 1)

Step 1.Tert-butyl(1-(1-(N-(tert-butoxycarbonyl)sulfamoyl)-3-(cyanomethyl)azetidin-3-yl)piperidin-4-yl)((1R,2S)-2-phenylcyclopropyl)carbamate(13)

tert-butyl ((1R,2S)-2-phenylcyclopropyl)(piperidin-4-yl) carbamate (fromExample 1, Step 3; 1.74 g, 5.47 mmol) and tert-butyl3-(cyanomethylene)azetidin-1-ylsulfonylcarbamate (from Intermediate 1,Step 2; 1.0 g, 3.65 mmol) and DBU (1.1 eq.) were dissolved inacetonitrile (3.0 ml, 3 V). The reaction mixture was heated to 55° C.and stirred for 18 h, after which time the reaction was judged completeby HPLC. The reaction mixture was cooled to room temperature. Aqueous0.3N HCl solution (6.0 ml, 6 V) was added dropwise. The mixture waspartitioned between EtOAc (10.0 mL) and water. The organics were washedwith 0.3N HCl and water, dried and concentrated to provide crudeproduct. The crude material was dissolved in THF (5V). Heptane was addedslowly to provide a beige solid. The mixture was stirred at roomtemperature for 6 h. The solid was isolated via filtration and washedwith heptane. The solid was dried to afford the title compound in 94%yield. LC-MS calculated for C₂₉H₄₃N₅O₆S [M+H]⁺ m/z: 590.7; found 590.3.¹H NMR (400 MHz, CDCl₃) δ 7.35-7.26 (m, 2H), 7.18-7.08 (m, 3H),4.18-4.09 (t, J=8.1 Hz, 2H), 3.98-3.88 (dd, J=7.7, 5.1 Hz, 2H),3.77-3.63 (tq, J=12.5, 4.8, 4.4 Hz, 1H), 2.83-2.71 (m, 4H), 2.62-2.53(m, 1H), 2.44-2.30 (tdd, J=11.0, 8.5, 2.4 Hz, 2H), 2.18-1.99 (m, 2H),2.00-1.77 (m, 3H), 1.53 (s, 9H), 1.48-1.18 (m, 12H).

Step 2.3-(Cyanomethyl)-3-(4-{[(1R,2S)-2-phenylcyclopropy]amino}piperidin-1-yl)azetidine-1-sulfonamidedihydrochloride (1)

tert-butyl(1-(1-(N-(tert-butoxycarbonyl)sulfamoyl)-3-(cyanomethyl)azetidin-3-yl)piperidin-4-yl)((1R,2S)-2-phenylcyclopropyl)carbamate(2.0 g, 4.08 mmol) was dissolved in methanolic HCl (3.0 M, 12.0 mL). Thereaction mixture was heated to 40° C. and stirred for 3 h, at which timethe reaction was judged complete by HPLC. After cooling to roomtemperature, a white precipitate formed. MTBE (36 mL, 18 V) was addedand the mixture was stirred at room temperature. Filtration provided thedesired product (1.44 g) in 92% yield. LC-MS calculated forC₁₉H₁₂₉Cl₂N₅O₂S [M+H]⁺ m/z: 390.1; found 390.1. ¹H NMR (400 MHz, D20) δ7.43-7.27 (m, 3H), 7.25-7.17 (m, 2H), 4.20-4.13 (d, J=9.8 Hz, 2H),4.09-4.01 (d, J=9.8 Hz, 2H), 3.71-3.58 (tt, J=11.9, 4.2 Hz, 1H),3.48-3.33 (m, 4H), 3.12-2.95 (dddt, J=23.8, 11.8, 8.0, 3.4 Hz, 3H),2.59-2.39 (m, 3H), 2.08-1.96 (m, 2H), 1.60-1.43 (m, 2H).

Example 3 Alternative Preparation of3-(cyanomethyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamide(Compound 1)

Step 1. Tert-butyl3-(cyanomethyl)-3-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)azetidine-1-carboxylate(16)

To a solution of tert-butyl 3-(cyanomethylene) azetidine-1-carboxylate(50.0 g, 257 mmol) in MeOH (500 mL) was added 1,4-dioxa-8-azaspiro[4.5]decane (36.85 g, 257 mmol). The reaction mixturewas heated to reflux for 8 hours, then cooled to room temperature. Water(1 L) was added to the reaction mixture. The mixture was stirred at roomtemperature for 5 h, and then filtered. The residue was used in the nextstep without further purification (72.8 g, 84% yield). LC-MS calculatedfor C₁₇H₂₇N₃O₄ [M+H]⁺ m/z: 338.2; found 338.2. ¹H NMR (400 MHz, CDCl₃) δ3.99 (s, 4H), 3.91-3.75 (m, 4H), 2.70 (s, 2H), 2.61-2.53 (t, J=5.5 Hz,4H), 1.79-1.71 (t, J=5.5 Hz, 4H), 1.49 (s, 9H).

Step 2. 2-(3-(4-oxopiperidin-1-yl)azetidin-3-yl)acetonitriledihydrochloride (15)

To a suspension of tert-butyl3-(cyanomethyl)-3-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)azetidine-1-carboxylate(10.0 g) in a solution of 5.2 N HCl in isopropanol (60 mL) was addedwater (30 mL) at room temperature. The reaction mixture was heated to60° C. for 30 minutes. The solution became cloudy, and solidprecipitated out. After stirring for another 1.5 h, the reaction mixturewas cooled to room temperature. Filtration and washing with isopropanolprovided a solid. The solid was dried in a vacuum oven (50° C.)overnight to provide the title compound (6.18 g, 78%). LC-MS calculatedfor C₁₀H₁₇Cl₂N₃O [M+H]⁺ m/z: 194.1; found 194.1. ¹H NMR (400 MHz, DMSO)δ 9.60 (s, 1H), 9.46 (s, 1H), 4.08-3.97 (dt, J=13.1, 7.2 Hz, 2H),3.93-3.81 (dd, J=18.8, 4.1 Hz, 2H), 3.22 (s, 2H), 2.87-2.79 (t, J=6.0Hz, 4H), 2.43-2.35 (t, J=5.9 Hz, 4H).

Step 3.Tert-butyl((3-(cyanomethyl)-3-(4-oxopiperidin-1-yl)azetidin-1-yl)sulfonyl)carbamate(14)

A stirring solution of tert-butyl alcohol (61.5 g, 830 mmol) indichloromethane (330 mL, 6V) was cooled with ice/salt water bath.Sulfurisocyanatidic chloride (64 mL, 734 mmol) dissolved in DCM (330 mL,6V) was slowly added with an addition funnel, holding the temperaturebetween 1.5° C. and 5.5° C. The solution was stirred for 1 h at 3° C.,providing a solution of tert-butyl chlorosulfonylcarbamate.

To a suspension of 2-(3-(4-oxopiperidin-1-yl)azetidin-3-yl)acetonitriledihydrochloride (from Step 2) (169.8 g, 638 mmol) in dichloromethane(1698 mL, 10V) was added triethylamine (231 mL, 1660 mmol). Afterstirring for 30 minutes, the reaction mixture was cooled to 0° C. Tothis mixture was added the prepared solution of tert-butylchlorosulfonylcarbamate with an addition funnel (2-13° C., controlled bythe addition rate) slowly. The reaction mixture was stirred at 0° C. for1 h after addition. The reaction mixture was diluted withdichloromethane (300 mL). The reaction mixture was partitioned betweendichloromethane and 0.2N HCl in water (3.55 L). The organics were driedover MgSO₄ and concentrated to give the title compound (235 g, 99%).LC-MS calculated for C₁₅H₂₄N₃₄O₅S [M+H]⁺ m/z: 373.1; found 373.1. ¹H NMR(400 MHz, CDCl₃) δ 7.01 (s, 1H), 4.23 (d, J=8.1 Hz, 2H), 3.97 (d, J=8.2Hz, 2H), 2.92-2.68 (m, 6H), 2.46 (t, J=5.9 Hz, 4H), 1.50 (s, 9H).

Step 4.Tert-butyl(1-(3-(cyanomethyl)-1-sulfamoylazetidin-3-yl)piperidin-4-yl)((1S,2S)-2-phenylcyclopropyl)carbamate(12)

To a solution of tert-butyl((3-(cyanomethyl)-3-(4-oxopiperidin-1-yl)azetidin-1-yl)sulfonyl)carbamate(24.96 g, 128 mmol) and (1R,2S)-2-phenylcyclopropan-1-amine (19.94 g,141 mmol) in dichloromethane (340 ml) was added acetic acid (15.38 ml,269 mmol) and the reaction mixture was stirred at room temperature for 1h. After this time, the reaction mixture was cooled to 0° C. Sodiumtriacetoxyhydroborate (32.5 g, 153 mmol) was added in four portions over30 min. The reaction mixture was stirred at 0° C. for 4 h, until thereaction was complete. 7% NaHCO₃ in water (200 mL) was added. Themixture was stirred for 30 min, after which time the organic and aqueousphases were separated. The organic phase was dried with sodium sulfate,filtered, and returned to a round bottom flask. Di-tert-butyldicarbonate (30.7 g, 141 mmol) was added, and the reaction mixture washeated to 40° C. The reaction mixture was stirred at 40° C. untilcomplete. The reaction mixture was then cooled to room temperature.Water (200 mL) was added. The organic and aqueous phases were separated.The organic phase was dried with sodium sulfate, filtered, andconcentrated to provide 50.8 g of oil of the title compound that wasused without further purification. LC-MS calculated for C₂₉H₄₃N₅O₆S[M+H]⁺ m/z: 590.3; found 590.3. ¹H NMR (400 MHz, CDCl₃) δ 7.35-7.26 (m,2H), 7.18-7.08 (m, 3H), 4.18-4.09 (t, J=8.1 Hz, 2H), 3.98-3.88 (dd,J=7.7, 5.1 Hz, 2H), 3.77-3.63 (tq, J=12.5, 4.8, 4.4 Hz, 1H), 2.83-2.71(m, 4H), 2.62-2.53 (m, 1H), 2.44-2.30 (tdd, J=11.0, 8.5, 2.4 Hz, 2H),2.18-1.99 (m, 2H), 2.00-1.77 (m, 3H), 1.53 (s, 9H), 1.48-1.18 (m, 12H).

Step 5.3-(Cyanomethyl)-3-(4-{[(1R,2S)-2-phenylcyclopropy]amino}piperidin-1-yl)azetidine-1-sulfonamidedihydrochloride (1)

Tert-butyl(1-(1-(N-(tert-butoxycarbonyl)sulfamoyl)-3-(cyanomethyl)azetidin-3-yl)piperidin-4-yl)((1R,2S)-2-phenylcyclopropyl)carbamate(2.0 g, 4.08 mmol) was dissolved in methanol (6 mL, 3 V) and methanolicHCl (3.0 M, 12.0 mL). The reaction mixture was heated to 40° C. andstirred for 3 h, at which time the reaction was judged complete by HPLC.After cooling to room temperature, a white precipitate formed. MTBE (36mL, 18 V) was added and the mixture was stirred at room temperature.Filtration provided the desired product (1.7 g, 3.68 mmol) in 90% yield.LC-MS calculated for C₁₉H₂₉Cl₂N₅O₂S [M+H]⁺ m/z: 390.1; found 390.1. ¹HNMR (400 MHz, D₂O) δ 7.43-7.27 (m, 3H), 7.25-7.17 (m, 2H), 4.20-4.13 (d,J=9.8 Hz, 2H), 4.09-4.01 (d, J=9.8 Hz, 2H), 3.71-3.58 (tt, J=11.9, 4.2Hz, 1H), 3.48-3.33 (m, 4H), 3.12-2.95 (dddt, J=23.8, 11.8, 8.0, 3.4 Hz,3H), 2.59-2.39 (m, 3H), 2.08-1.96 (m, 2H), 1.60-1.43 (m, 2H).

Example 4 Preparation and Characterization of Form I

3-(Cyanomethyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamidedihydrochloride (15.68 g, 33.90 mmol) was dissolved in methanol (5000mmol) while heating to reflux, and then polish filtrated.2-Methoxy-2-methylpropane (2000 mmol) was then slowly added while solidcrashed out and the mixture was stirred overnight. Solids were thencollected by filtration and dried on the filter overnight to give FormI.

The solid product was confirmed as a crystalline solid having Form Iaccording to XRPD analysis. The XRPD pattern of Form I is shown in FIG.1 and the peak data is given below in Table 1.

TABLE 1 XRPD Peak Data for Form I 2-Theta Height I % 3.8 71.0 15.4 5.9461.0 100.0 7.1 77.0 16.7 9.9 44.0 9.5 12.5 36.0 7.8 13.2 50.0 10.8 15.163.0 13.7 15.9 39.0 8.5 16.9 80.0 17.4 18.2 107.0 23.2 20.3 52.0 11.320.7 70.0 15.2 23.5 142.0 30.8 24.7 39.0 8.5 25.2 68.0 14.8 26.1 124.026.9 29.7 64.0 13.9 32.0 40.0 8.7

Form I exhibits a DSC thermogram having endotherm peaks at temperaturesof about 80° C. and about 175° C. and an exotherm peak at a temperatureof about 197° C. FIG. 2 shows a DSC thermogram of Form I. FIG. 3 shows aTGA thermogram of Form I.

Example 5 Preparation and Characterization of Form II

3-(Cyanomethyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamidedihydrochloride (532.9 g, 729.1 mmol; See Example 1) was mixed with2-butanone (7223 mL). The mixture was heated to 55° C. (internaltemperature set) to become a clear solution. The hot solution was polishfiltered through an inline filter, and the clear solution was distilledoff under vacuum to about 4 L volume while being heated at 55° C. To thesolution was added heptane (4676 mL) while stirring. After the addition,the mixture was kept at 55° C. for 4 hours, then allowed to cool to roomtemperature. The mixture was stirred overnight. The solid was filteredand washed with a mixture of heptane (1000 mL) and 2-butanone (1000 mL).The product was dried on the filter overnight, and then under highvacuum at 50° C. overnight to give Form II.

The solid product was confirmed as a crystalline solid having Form IIaccording to XRPD analysis. The XRPD pattern of Form II is shown in FIG.4 and the peak data is given below in Table 2.

TABLE 2 XRPD Peak Data for Form II 2-Theta Height I % 5.8 69.0 94.5 13.230.0 41.1 15.1 50.0 68.5 17.1 50.0 68.5 20.1 58.0 79.5 20.8 60.0 82.222.5 68.0 93.2 25.4 73.0 100.0 28.0 41.0 56.2 29.1 37.0 50.7

Form II exhibits a DSC thermogram having an exotherm peak at atemperature of about 198° C. FIG. 5 shows a DSC thermogram of Form I.FIG. 63 shows a TGA thermogram of Form I.

Example 6 Solubility Measurement

The solubility of Compound 1 di-HCl was measured at 25±1° C. and 50±1°C. according to the following procedures.

Solubility at 25±1° C.

Compound 1 di-HCl was added to 2 mL of a solvent listed in Table 3 at25±1° C. until the solution became cloudy. Another 10 mg of Compound 1di-HCl was then added. The mixture was agitated at 25±1° C. for 36 h.The supernatant was filtered using a syringe filter. The saturatedsolution was pipetted into an HPLC vial, which was diluted withacetonitrile. The solubility of Compound 1 di-HCl was calculated foreach solvent. The calculated solubilities at 25±1° C. are shown in Table3.

Solubility at 50±1° C.

Compound 1 di-HCl was added to 2 mL of a solvent listed in Table 3 at50±1° C. until the solution became cloudy. Another 20-25 mg of Compound1 di-HCl was then added. The mixture was agitated at 50±1° C. for 24 h.The supernatant was filtered using a warmed syringe filter at 50±1° C.The saturated solution was pipetted into an HPLC vial, which was dilutedwith acetonitrile. The solubility of Compound 1 di-HCl was calculatedfor each solvent. The calculated solubilities at 50±1° C. are shown inTable 3.

TABLE 3 Solubility of Compound 1 di-HCl in Various Solvents Solubilityat 25° C. Solubility at 50° C. Solvent (mg/mL) (mg/mL) MeCN 0.61 6.29Chloroform >50*    >50*    Dichloromethane 0.00 0.06 DMF >50*    >50*   1,4-Dioxane 0.20 0.31 Methanol 32.32  >50    2-Methoxyethanol 45.92 48.27  MIBK 0.06 0.13 Toluene 0.00 0.00 Hexane 0.00 0.00 THF 0.04 0.09Acetone 3.49 0.85 n-BuOH 1.31 2.34 MTBE 0.00 0.00 DMSO >50*    >50*   EtOH 3.37 3.63 EtOAc 0.00 0.03 Ethyl formate 0.09 0.05 Heptane 0.00 0.00Isobutyl acetate 0.00 0.00 IPAc 0.00 0.00 1-Propanol 4.60 5.21 IPA 1.311.91 Water >50*    >50*    MEK 0.16 0.16 MeOH/water/ACN >50*    >50*   (6 v/1.5 v/3 v) Me0H/water/ACN >50*    >50*    (5 v/2 v/3 v)MeOH/water/ACN >50    >50*    (6 v/1 v/3 v)MeOH/water/ACN >50*    >50*    (6 v/0.5 v/3.5 v) MeOH/ACN (10 v/3v) >50*    >50*    ACN/water (9:1) >50*    >50*    5% Water inACN >50    45.39  5% Water in MeOH >50*    >50*    ACN:Water(4:1) >50*    >50*    MeOH/Water/ACN >50*    >50*    (6.0/0.5/1.0) *byvision

Example 7 Phase Equilibration at 25±1° C. and 50±1° C.

Phase equilibration studies were designed to provide information on apredominant crystal form for phase identification. Based on itssolubility in various solvent systems (Table 3), Compound 1 di-HCl wasequilibrated in a representative group of solvents at 25±1° C. (Table 4)and 50±1° C. (Table 5). To the solvents listed in Table 4 (25±1° C.) andTable 5 (50±1° C.) was added Compound 1 di-HCl until a cloudy solutionwas obtained, then, about 15-20 mg of Compound 1 di-HCl was added to thecloudy solution. The mixture was stirred at 25±1° C. for 2 days and50±1° C. for 1 day. The solid was filtered under nitrogen and analyzedby XRPD to give the results in Table 4 and Table 5.

Three new polymorphic forms were found by XRPD in the phaseequilibration at 25±1° C. including Form III (1,4-dioxane, n-BuOH, EtOH,IPAc, and IPA), Form IV (toluene), and Form V (MTBE). Phaseequilibration at 50±1° C. resulted in Form III (1,4-dioxane and MEK),Form IV (toluene), and Form V (MTBE).

TABLE 4 Crystal form for phase equilibration at 25 ± 1° C. Solvent SolidState Form Acetonitrile N/A Chloroform N/A DCM II 1,4-Dioxane IIIMethanol N/A 2-Methoxy-ethanol N/A MIBK II Toluene IV Hexane II THF IIAcetone II n-BuOH III MTBE V EtOH III EtOAc I Ethyl formate I Heptane IIIsobutyl acetate II IPAc III 1-Propanol II IPA III water N/A MEK IMeOH/water/ACN (6 v/1.5 v/3 v) N/A MeOH/water/ACN (5 v/2 v/3 v) N/AMeOH/water/ACN (6 v/1 v/3 v) N/A MeOH/water/ACN N/A (6 v/0.5 v/3.5 v)MeOH/ACN (10 v/3 v) N/A ACN/water (9:1) N/A Acetone/water (1:4) II 5%water in MeOH N/A ACN:water (4:1) N/A MeOH/water/ACN (6.0/0.5/1.0) N/AN/A: Not available. Ether clear solution/oil or the amount of theprecipitate was too small to be analyzed by XRPD.

TABLE 5 Crystal form for phase equilibration at 50 ± 1° C. Solvent SolidState Form Acetonitrile II Chloroform II DCM II 1,4-Dioxane III MethanolN/A 2-Methoxy-ethanol N/A MIBK II Toluene IV Hexane II THF II Acetone IIn-BuOH II MTBE V EtOH II EtOAc I Ethyl formate I Heptane I Isobutylacetate II IPAc II 1-propanol II IPA II water N/A MEK III MeOH/water/ACN(6 v/1.5 v/3 v) N/A MeOH/water/ACN (5 v/2 v/3 v) N/A MeOH/water/ACN (6v/1 v/3 v) N/A MeOH/water/ACN (6 v/0.5 v/3.5 v) N/A MeOH/ACN (10 v/3 v)N/A ACN/water (9:1) N/A 5% water in ACN II 5% water in MeOH N/AACN:water (4:1) N/A MeOH/water/ACN (6.0/0.5/1.0) N/A N/A: Not available.Ether clear solution/oil or the amount of the precipitate was too smallto be analyzed by XRPD.

Example 8 Evaporation at 25±1° C. and 50±1° C.

Evaporation studies were carried out to identify the predominant crystalform during uncontrolled precipitation. Experiments that did not resultin any particulate solids (i.e. clear thin films and oils) were notstudied further. XRPD was used to study the solid-state morphology ofthe crystalline forms of the evaporation samples at 25±1° C. and 50±1°C. The results are presented in Table 6 (25±1° C.) and Table 7 (50±1°C.).

The evaporation in the selected 19 solvents at 25±1° C. (Table 6) led toamorphous solid, oil or sticky solid. Evaporation in 22 solvents at50±1° C. resulted in Form I, II, and amorphous solid as indicated inTable 7.

TABLE 6 Crystal form identification from evaporation at 25 ± 1° C.Solvent Solid State Form Acetonitrile N/A Methanol Sticky solid2-Methoxyethanol Sticky solid Acetone N/A Solvent Solid State Formn-BuOH N/A EtOH N/A 1-Propanol Sticky solid IPA N/A water Brown oilMeOH/water/ACN Brown oil (6 v/1.5 v/3 v) MeOH/water/ACN Brown oil (5 v/2v/3 v) MeOH/water/ACN Brown oil (6 v/1 v/3 v) MeOH/water/ACN Brown oil(6 v/0.5 v/3.5 v) MeOH/ACN (10 v/3 v) Brown oil ACN/water (9:1) Brownoil 5% water in ACN Brown oil 5% water in MeOH Brown oil ACN:water (4:1)Brown oil MeOH/water/ACN Brown oil (6 v/0.5 v/1.0 v) N/A: Not available.Ether clear solution or the amount of the precipitate was too small tobe analyzed by XRPD.

TABLE 7 Crystal form identification from evaporation at 50 ± 1° C.Solvent Solid State Form Acetonitrile N/A Chloroform Amorphous solid DMFAmorphous solid Methanol Amorphous solid 2-Methoxyethanol II Acetone N/An-BuOH N/A DMSO N/A EtOH N/A 1-Propanol Amorphous solid IPA N/A waterAmorphous solid MeOH/water/ACN Amorphous solid (6 v/1.5 v/3 v)MeOH/water/ACN Amorphous solid (5 v/2 v/3 v) MeOH/water/ACN Amorphoussolid (6 v/1 v/3 v) MeOH/water/ACN Amorphous solid (6 v/0.5 v/3.5 v)MeOH/ACN (10 v/3 v) II ACN/water (9:1) Amorphous solid 5% water in ACNSticky solid 5% water in MeOH Amorphous solid ACN:water (4:1) Amorphoussolid Solvent Solid State Form MeOH/water/ACN Amorphous solid (6 v/0.5v/1.0 v) N/A: Not available. Ether clear solution or the amount of theprecipitate was too small to be analyzed by XRPD.

Example 9 Anti-Solvent Addition

Saturated solution or nearly saturated solution of Compound 1 di-HCl wasprepared by adding the compound (Compound 1 di-HCl Form I) to thesolvents in Table 8 respectively. An anti-solvent was added to induceprecipitation. MTBE, toluene and IPAc were selected as theanti-solvents. Experiments that did not produce any particulate solidson anti-solvent addition were not studied further, and all solids werefiltered under nitrogen. The results are presented in

TABLE 8 Antisolvent Addition of Compound 1 di-HCl in Various SolventsAnti-Solvent Solvent (mL) (mL) Solid State Form Chloroform MTBE II (1.0)(4.0) Methanol (0.5) MTBE (1.0) III Methanol (1.0) Toluene (8.0) Turbidsolution Methanol (1.0) IPAc II (7.0) 2-Methoxy-ethanol MTBE II (0.5)(2.0) 2-Methoxy-ethanol Toluene Clear solution (1.0) (7.0)2-Methoxy-ethanol IPAc II (0.5) (4.0) MeOH/water/ACN IPAc Sticky solid(6 V/1.5 V/3 V, 1.0 mL)) (12) MeOH/water/ACN MTBE Sticky solid (6 V/1.5V/3 V, 1.0 mL) (12) MeOH/water/ACN MTBE II (5 V/2 V/3 V, 1 mL) (10)(filtered under nitrogen) MeOH/water/ACN IPAc Sticky solid (5 V/2 V/3 V,1.0 mL) (5.0) MeOH/water/ACN MTBE I (6 V/1 V/4 V, 1 mL) (5.0) ( stirredfor 5 h, filtered under nitrogen)) MeOH/water/ACN IPAc II (6 V/1 V/4 V,1.0 mL) (12 mL) (filtered under nitrogen) MeOH/water/ACN MTBE II (6V/0.5 V/3.5 V, 1.0 mL)) (5.0) (stirred for 30 minutes to give goodsolid, filtered under nitrogen)) MeOH/water/ACN IPAc II (6 V/0.5 V/3.5V, 1.0 mL)) (7.0) (filtered under nitrogen) MeOH/ACN IPAc II (10 V/3.0V, 1.0 mL)) (7.0) (filtered under nitrogen) MeOH/ACN MTBE Amorphoussolid (10 V/3.0 V, 1.0 mL) (6.0) MeOH/ACN Toluene Turbid solution (10V/3.0 V, 1 mL)) (7.0) ACN/water MTBE N/A (9.0 V/1.0 V, 1.0 mL) (5.0 mL)ACN/water IPAc (7 mL) N/A (9.0 V/1.0 V, 1.0 mL) 5% water in ACN MTBE I(1.0 mL) (10) 5% water in CAN IPAc Sticky solid after being (1.0 mL)(6.0 mL) filtered 5% water in MeOH Toluene N/A (1.0 mL) (7.0 mL) 5%water in MeOH MTBE (2.5) II (0.5 mL) (Stirred for 30 minutes andfiltered under nitrogen) 5% water in MeOH, IPAc (10) Amorphous solid 1.0mL) MeOH/water/ACN MTBE Sticky solid (6 v/0.5 v/1.0, 1.0 ml) (12)MeOH/water/ACN IPAc Sticky solid (6 v/0.5 v/1.0, 1.0 mL) (12) N/A: Notavailable. Ether clear solution or the amount of the precipitate was toosmall to be analyzed by XRPD.

Example 10 Reverse Addition

Saturated solution and nearly saturated solution of Compound 1 di-HClwere prepared in the solvents listed in Table 9, and added to a largervolume of a miscible anti-solvent. MTBE, toluene and IPAc were selectedas the anti-solvents. Experiments that did not produce any particulatesolids upon addition to the anti-solvent were not studied further, andall solids were filtered under nitrogen.

TABLE 9 Reverse addition of Compound 1 di-HCl in various solventsSolvent (mL) Anti-Solvent (mL) Solid State Form Chloroform MTBE (5)Amorphous solid (1.0) (filtered under nitrogen) Chloroform IPAc (5.0)Turbid solution (1.0) Methanol MTBE (5) Amorphous solid (1.0) (filteredunder nitrogen) Methanol IPAc Clear solution (1.0) (5.0)2-Methoxy-ethanol (1.0) MTBE Sticky solid (5.0) 2-Methoxy-ethanol (1.0)Toluene Turbid solution (5.0) 2-Methoxy-ethanol (0.4) IPAc Oil (5.0)MeOH/water/ACN IPAc Turbid solution (6 V/1.5 V/3 V) (5.0) (1.0)MeOH/water/ACN MTBE Turbid solution (6 V/1.5 V/3 V, 1.0) (5.0)MeOH/water/ACN MTBE Turbid solution (5 V/2 V/3 V, 1.0 mL) (5.0)MeOH/water/ACN IPAc Turbid solution (5 V/2 V/3 V, 1.0 mL) (5.0)MeOH/water/ACN MTBE Sticky solid (6 V/1 V/4 V, 0.2 mL) (5.0)MeOH/water/ACN IPAc Amorphous solid (6 V/1 V/4 V, 0.2 mL) (5.0)(filtered under nitrogen) MeOH/water/ACN MTBE Amorphous solid (6 V/0.5V/3.5 V, 1.0 mL) (5.0) (filtered under nitrogen) MeOH/water/ACN IPAcII + Amorphous solid (6 V/0.5 V/3.5 V, 1.0 mL) (5.0) (filtered undernitrogen) MeOH/ACN IPAc II (10 V/3.0 V, 1.0 mL) (5.0) (filtered undernitrogen) MeOH/ACN MTBE II (10 V/3.0 V, 1.0 mL) (5.0) (filtered undernitrogen) MeOH/ACN Toluene Turbid solution (10 V/3.0 V, 1.0 mL) (5.0)ACN/water MTBE Amorphous solid (9.0 V/1.0 V) (5.0) (filtered undernitrogen) (0.2 mL) ACN/water IPAc Amorphous solid (9.0 V/1.0 V) (5.0)(filtered under nitrogen) (0.2 mL) 5% water in ACN MTBE Turbid solution(0.8 mL) (5.0) 5% water in MeOH Toluene Oil (1.2 mL) (5.0) 5% water inMeOH MTBE Amorphous solid (0.4 mL) (5.0) (filtered under nitrogen) 5%water in MeOH IPAc Amorphous solid (0.2 mL) (5.0) (filtered undernitrogen) ACN/water Toluene Sticky solid (4.0 V/1.0 V, 0.6 mL) (5.0)ACN/water MTBE Sticky solid (4.0 V/1.0, 1.0 mL) (5.0) MeOH/water/ACNIPAc Sticky solid (6 v/0.5 v/1.0 v, 1 mL) (7.0) N/A: Not available.Ether clear solution or the amount of the precipitate was too small tobe analyzed by XRPD.

Example 11 Quenching of Saturated Solution

Saturated solution and nearly saturated solution of Compound 1 di-HClForm I prepared at about 30° C. were quenched to about −20° C. to induceprecipitation of higher energy forms. Representative solvents in Table10 were chosen based on solubility data measured at 25° C. The quenchingof the saturated and nearly saturated solution for all of solvents hasnot resulted in any solid.

TABLE 10 Result for Compound 1 di-HCl Form I from quenching SolventResult MeCN Clear solution Methanol Clear solution MeOH/water/ACN(6v/1.5v/3v) Clear solution MeOH/water/ACN (5v/2v/3v) Clear solutionMeOH/water/ACN (6v/1v/3v) Clear solution MeOH/water/ACN (6v/0.5v/3.5v)Clear solution MeOH/ACN (10v/3v) Clear solution ACN/water (9:1) Clearsolution 5% water in ACN Clear solution 5% water in MeOH Clear solutionACN:water (4:1) Clear solution MeOH/water/ACN (6.0/0.5/1.0) Clearsolution

Example 12 Crystallization of Saturated Solution with Heating andCooling Cycles

This experiment was designed to search further for a more stable formthan Form I and Form II. Saturated and nearly saturated solutions ofCompound 1 di-HCl Form I were prepared at 50° C., and cooled in a bathslowly by using a programmed circulating bath. To the clear solution(about 5 mL) was added about 20-30 mg Compound 1 di-HCl Form Ito giveslurry. The formed slurry was then heated to 50° C. over 2 hours andthen cooled down to 5° C. over 2 hours. This process was repeated for 3days and the solid was filtered under nitrogen for further analysis. Theresults are presented in Table 11.

TABLE 11 Crystallization of saturated solution of Compound 1 di-HCl withheating and cooling recycles Solvent Form 2-methoxyethanol I Acetone In-BuOH I ethanol I Ethyl formate I 1-propanol I 2- propanol II MEK I 5%water in ACN II

Example 13 Preparation and Characterization of Form III

To about 3.5 mL of cloudy solutions of Compound 1 di-HCl prepared in1,4-dioxane was added about 15-20 mg of Compound 1 di-HCl followed bystirring at 25±1° C. for 2 days, which was filtered under nitrogen andanalyzed by XRPD as Form III. The XRPD pattern of Form III is shown inFIG. 7 and the peak data is given below in Table 12.

TABLE 12 XRPD Peak Data for Form III 2-Theta Height I % 5.4 2179.0 78.86.7 93.0 3.4 16.4 60.0 2.2 16.8 350.0 12.7 18.2 82.0 3.0 19.5 57.0 2.121.9 2765.0 100.0 22.2 538.0 19.5 23.3 56.0 2.0 27.4 153.0 5.5 27.7234.0 8.5 28.6 369.0 13.3 33.1 138.0 5.0 36.8 31.0 1.1 39.0 232.0 8.439.6 67.0 2.4

Example 14 Preparation and Characterization of Form IV

To about 3.5 mL of cloudy solutions of drug substance prepared intoluene was added about 15-20 mg of Compound 1 di-HCl followed bystirring at 25±1° C. for 2 days, which was filtered under nitrogen andanalyzed by XRPD as Form IV. The XRPD pattern of Form IV is shown inFIG. 8 and the peak data is given below in Table 13.

TABLE 13 XRPD Data for Form IV 2-Theta Height I % 5.8 32.0 40.0 17.464.0 80.0 18.3 38.0 47.5 20.9 79.0 98.8 21.4 54.0 67.5 22.5 76.0 95.024.2 57.0 71.3 25.6 44.0 55.0 26.9 80.0 100.0 29.2 44.0 55.0 30.5 42.052.5 39.7 30.0 37.5

Example 15 Preparation and Characterization of Form V

To about 3.5 mL of cloudy solutions of Compound 1 di-HCl prepared inMTBE was added about 15-20 mg of drug substance followed by stirring at25±1° C. for 2 days, which was filtered under nitrogen and analyzed byXRPD as Form V. The XRPD pattern of Form V is shown in FIG. 9 and thepeak data is given below in Table 14.

TABLE 14 XRPD Data for Form V 2-Theta Height I % 4.1 60.0 34.9 5.4 172.0100.0 6.8 41.0 23.8 13.1 52.0 30.2 15.2 62.0 36.0 16.7 54.0 31.4 17.337.0 21.5 20.5 45.0 26.2 21.7 78.0 45.3 25.6 68.0 39.5 31.9 35.0 20.3

Form V exhibits a DSC thermogram having an exotherm peak at atemperature of about 198° C. FIG. 10 shows a DSC thermogram of Form V.FIG. 11 shows a TGA thermogram of Form V.

Example 16 Stability Relationship Between Forms II-V

The transformation of Compound 1 di-HCl solid forms was evaluated incompetitive slurry experiments in methanol at 23-25° C. and 65-75%humidity. The experiments were performed with a mixture of fourpolymorphs (Form II through Form V), according to the followingprocedure.

10.0 mg of Compound 1 di-HCl Form II was added to a saturated solutionof Compound 1 di-HCl Form II in methanol (1.0 mL) and stirred to give athin slurry. A mixture of Form III (10.29 mg), Form IV (10.39 mg), andForm V (10.95 mg) were added to the slurry. The mixture was stirred for4 h at 25° C.

A portion of the mixture was filtered after 4 h. The filtered solidswere analyzed by XRPD and determined to be Form II in addition to aminor amount of amorphous solid.

A portion of the mixture was filtered after 20 h. The filtered solidswere analyzed by XRPD and determined to be Form II in addition to aminor amount of amorphous solid. The sample was then dried under vacuumat 46-48° C. for 36 h. The dried solids were analyzed by XRPD anddetermined to be Form II.

Form II was the most stable form among the forms identified.

Example 17 Conversion of Compound 1 di-HCl to Compound 1 (free base)

50 mL of H₂O was added to Compound 1 di-HCl (6500 mg) and allowed toslurry for 10 min to give a clear solution. An aqueous solution ofNaHCO₃ (75 mL; 8.7% solution in water; 5.5 equiv) was added to thesolution and stirred to give a slurry. The mixture was allowed to stirfor 20 min. The mixture was filtered and the solids were washed withdeionized water (4×40 mL) until the pH was about 6-7. The solids wereair dried for 4 days to provide Compound 1 as the free base in 92.5%yield (5.05 g).

The solid product was confirmed as a crystalline solid according to XRPDanalysis. The XRPD pattern of Compound 1 (free base) is shown in FIG. 37and the peak data is given below in Table 15.

TABLE 15 XRPD Peak Data for Compound 1 (free base) 2-Theta Height I %4.2 767 100 21.7 78 10.2

Compound 1 (free base) exhibits a DSC thermogram having an endothermpeak at a temperature of about 159° C. FIG. 38 shows a DSC thermogram ofCompound 1 (free base). FIG. 39 shows a TGA thermogram of Compound 1(free base).

Example 18 Preparation and Characterization of Compound 1 Di-Mesylate

Compound 1 (50.03 mg, 0.128 mmol) was dissolved in 1.0 mLdichloromethane and 0.8 mL of methanol to give a clear solution.Methanesulfonic acid (0.32 mL, 1 M in IPA, 0.32 mmol, 2.5 eq) was addedto the solution. The mixture was stirred at room temperature for 4 h togibe a slurry. Dichloromethane was removed using rotary evaporation togive a slurry. The slurry was allowed to stir for 2 h. The slurry wasfiltered, and the solids were dried at 40-45° C. under vacuum overnightto provide Compound 1 di-mesylate as a crystalline solid (63.5 mg,84.98%).

The solid product was confirmed as a crystalline solid according to XRPDanalysis. The XRPD pattern of compound 1 di-mesylate is shown in FIG. 12and the peak data is given below in Table 16.

TABLE 16 XRPD Peak Data for compound 1 di-mesylate 2-Theta Height I %3.9 59.0 34.3 5.8 172.0 100.0 11.8 47.0 27.3 14.3 35.0 20.3 15.8 59.034.3 19.1 69.0 40.1 20.2 50.0 29.1 21.9 154.0 89.5 22.8 53.0 30.8 25.261.0 35.5 25.9 43.0 25.0

Compound 1 di-mesylate exhibits a DSC thermogram having an endothermpeak at a temperature of about 201° C. FIG. 13 shows a DSC thermogram ofCompound 1 di-mesylate. FIG. 14 shows a TGA thermogram of Compound 1di-mesylate.

Example 19 Preparation of Compound 1 di-HCl Form I from Compound 1 (FreeBase)

MeOH (2.0 mL) was added to 100 mg of Compound 1. A solution of HCl (0.67mL, 1.0 M in isopropyl alcohol, 2.6 eq). The solution was stirred atroom temperature for 3 h. MTBE (4 mL) was added and the mixture wasallowed to stir for 3 h. The mixture was filtered, and the cake wasdried at 40-45° C. under vacuum overnight to provide Compound 1 di-HClForm I (99.5 mg, 83.81%). Characterization data for Form I is providedin Example 4.

Example 20 Preparation and Characterization of Compound 1 Malonate

Dichloromethane (1.0 mL) and IPA (1.0 mL) were added to Compound 1(50.07 mg, 0.131 mmol). Malonic acid (34.12 mg, 0.32 mmol, 2.5 eq) wasadded and the solution was allowed to stir at room temperature for 5 h.Dichloromethane was removed at 40° C. to give a slurry. The slurry wasallowed to stir for 2 h. The slurry was filtered and washed with MTBE(2.0 mL). The solids were dried at 40-45° C. under vacuum overnight toprovide Compound 1 malonate (54.0 mg) in 85.11% yield.

The solid product was confirmed as a crystalline solid according to XRPDanalysis. The XRPD pattern of Compound 1 malonate is shown in FIG. 15and the peak data is given below in Table 17.

TABLE 17 XRPD Data for Compound 1 Malonate 2-Theta Height I % 4.9 202.034.9 13.1 57.0 9.9 14.8 132.0 22.8 15.4 48.0 8.3 16.1 124.0 21.5 16.8133.0 23.0 17.7 578.0 100.0 18.3 87.0 15.1 20.0 199.0 34.4 21.5 70.012.1 22.2 238.0 41.2 24.5 210.0 36.3 25.0 159.0 27.5 26.3 63.0 10.9 27.7128.0 22.1 29.8 197.0 34.1 34.4 46.0 8.0 35.6 36.0 6.2 38.0 63.0 10.9

Compound 1 malonate exhibits a DSC thermogram having an endotherm peakat a temperature of about 147° C. FIG. 16 shows a DSC thermogram ofCompound 1 malonate. FIG. 17 shows a TGA thermogram of Compound 1malonate.

Example 21 Preparation and Characterization of Compound 1 Mono-HCl

Dichloromethane (1.8 mL) and IPA (1.8 mL) were added to 100 mg ofCompound 1 (0.257 mmol). HCl (0.27 mL, 1 M in IPA, 0.27 mmol, 1.05 eq)was added to the solution. The solution was allowed to stir at roomtemperature for 2 h. Dichloromethane was removed at 40° C. to give aslurry. The slurry was stirred for 2 h, filtered, and washed with MTBE(2.0 mL). The solids were dried at 40-45° C. under vacuum overnight toprovide Compound 1 mono-HCl (93.04 mg) in 85.07% yield.

The solid product was confirmed as a crystalline solid according to XRPDanalysis. The XRPD pattern of Compound 1 mono-HCl is shown in FIG. 18and the peak data is given below in Table 18.

TABLE 18 XRPD Data for Compound 1 mono-HCl 2-Theta Height I % 10.3 305.049.1 11.4 100.0 16.1 12.1 93.0 15.0 12.8 251.0 40.4 14.2 122.0 19.6 15.6570.0 91.8 16.4 621.0 100.0 16.9 56.0 9.0 18.4 152.0 24.5 19.3 397.063.9 21.5 574.0 92.4 22.8 331.0 53.3 23.5 202.0 32.5 24.2 259.0 41.725.3 200.0 32.2 25.7 438.0 70.5 27.2 274.0 44.1 28.1 80.0 12.9 29.6113.0 18.2 30.8 129.0 20.8 31.9 154.0 24.8 32.4 134.0 21.6 33.0 74.011.9 34.5 80.0 12.9 36.4 143.0 23.0 37.2 79.0 12.7 39.7 47.0 7.6 40.690.0 14.5 41.5 33.0 5.3 43.9 63.0 10.1

Compound 1 mono-HCl exhibits a DSC thermogram having an exotherm peak ata temperature of about 178° C. and an endotherm peak at a temperature ofabout 204° C. FIG. 19 shows a DSC thermogram of Compound 1 mono-HCl.FIG. 20 shows a TGA thermogram of Compound 1 mono-HCl.

Example 22 Preparation and Characterization of Compound 1 Esylate

MeOH (0.5 mL) was added to Compound 1 (50.47 mg, 0.130 mmol).Ethanesulfonic acid (0.35 mL, 0.175 mmol, 1.35 eq, 0.5 M in IPA) wasadded and stirred for about 2 min to provide a clear solution. Thesolution was stirred for about 8 min to give a slurry. The slurry wasthen stirred for 3 h. The slurry was filtered, and the solids were driedat 40-45° C. under vacuum overnight to provide the Compound 1 esylate(52.0 mg) in 80.33% yield.

The solid product was confirmed as a crystalline solid according to XRPDanalysis. The XRPD pattern of Compound 1 esylate is shown in FIG. 21 andthe peak data is given below in Table 19.

TABLE 19 XRPD Data for Compound 1 Esylate. 2-Theta Height I % 4.7 136.061.0 9.4 105.0 47.1 12.3 79.0 35.4 14.7 68.0 30.5 16.1 93.0 41.7 16.789.0 39.9 18.0 70.0 31.4 18.9 107.0 48.0 20.5 149.0 66.8 21.7 223.0100.0 22.8 178.0 79.8 24.6 126.0 56.5 25.9 43.0 19.3 27.2 52.0 23.3 28.638.0 17.0 29.1 35.0 15.7 30.7 99.0 44.4 34.3 46.0 20.6 35.6 27.0 12.137.6 43.0 19.3 38.8 61.0 27.4 39.3 57.0 25.6 44.2 33.0 14.8

Compound 1 Esylate exhibits a DSC thermogram having an endotherm peak ata temperature of about 185° C. and an exotherm peak at a temperature ofabout 190° C. FIG. 22 shows a DSC thermogram of Compound 1 esylate. FIG.23 shows a TGA thermogram of Compound 1 esylate.

Example 23 Preparation and Characterization of Compound 1 Maleate

MeOH (0.6 mL) was added to Compound 1 (51.05 mg, 0.133 mmol). Maleicacid (20.81 mg, 0.176 mmol, 1.34 eq, 98% purity) was added and stirredfor two minutes to provide a clear solution. The solution was stirred atroom temperature for 30 min. IPA (0.8 mL) was added and allowed to stir.Methanol was removed at 40-45° C. under vacuum unit the total volume wasabout 1.0-1.1 mL. The resulting cloudy solution was cooled to roomtemperature and IPA (0.6 mL) was added, resulting in a slurry. Theslurry was stirred at 60° C. for 20 min, and then at room temperaturefor 3 h. The mixture was filtered, and the solids were dried at 40-45°C. under vacuum overnight to provide Compound 1 maleate (62.68 mg) in94.59% yield.

The solid product was confirmed as a crystalline solid according to XRPDanalysis. The XRPD pattern of Compound 1 maleate is shown in FIG. 24 andthe peak data is given below in Table 20.

TABLE 20 XRPD Data for Compound 1 Maleate 2-Theta Height I % 3.8 46.07.7 9.9 75.0 12.5 11.5 180.0 30.0 15.3 461.0 76.7 16.3 101.0 16.8 18.4384.0 63.9 19.0 132.0 22.0 19.6 129.0 21.5 20.7 389.0 64.7 21.5 196.032.6 22.9 601.0 100.0 24.7 123.0 20.5 25.2 331.0 55.1 27.1 56.0 9.3 29.0162.0 27.0 30.6 266.0 44.3 34.2 167.0 27.8 36.2 100.0 16.6 37.4 44.0 7.342.1 49.0 8.2

Compound 1 maleate exhibits a DSC thermogram having an endotherm peak ata temperature of about 158° C. FIG. 25 shows a DSC thermogram ofCompound 1 maleate. FIG. 26. shows a TGA thermogram of Compound 1maleate.

Example 24 Preparation and Characterization of Compound 1 Camsylate

(+)-(1S)-Camphorsulfonic acid (1.0 M in water, 0.14 mmol, 0.14 mL, 2.09eq) was added dropwise to a solution of Compound 1 (26.10 mg, 0.067mmol, 1.0 eq) in a mixture of dichloromethane (0.5 mL) and methanol (0.5mL) to give Compound 1 camsylate.

The solid product was confirmed as a crystalline solid according to XRPDanalysis. The XRPD pattern of Compound 1 camsylate is shown in FIG. 27and the peak data is given below in Table 21.

TABLE 21 XRPD Data for Compound 1 Camsylate 2-Theta Height I % 4.0 359.090.0 7.8 307.0 76.9 8.5 90.0 22.6 11.4 50.0 12.5 12.8 51.0 12.8 14.2201.0 50.4 15.3 65.0 16.3 16.1 252.0 63.2 16.7 185.0 46.4 17.3 120.030.1 19.5 399.0 100.0 20.2 143.0 35.8 21.2 342.0 85.7 21.8 170.0 42.622.5 232.0 58.1 24.1 109.0 27.3 25.1 130.0 32.6 25.7 106.0 26.6 26.7138.0 34.6 27.3 90.0 22.6 29.2 96.0 24.1 30.5 65.0 16.3 31.7 51.0 12.832.4 36.0 9.0 33.6 43.0 10.8 34.4 82.0 20.6 36.3 91.0 22.8 37.2 62.015.5 40.3 59.0 14.8 41.1 36.0 9.0 44.3 41.0 10.3

Compound 1 camsylate exhibits a DSC thermogram having an endotherm peakat a temperature of about 168° C. FIG. 28 shows a DSC thermogram ofCompound 1 camsylate. FIG. 29 shows a TGA thermogram of Compound 1camsylate.

Example 25 Preparation and Characterization of Compound 1 Isethionate

Isethionic acid (95% purity, 80% in water, 24.01 mg, 0.145 mmol, 2.16eq) was added to a solution of Compound 1 (26.10 mg, 0.067 mmol, 1.0 eq)in a mixture of DCM (0.5 mL) and methanol (0.5 mL) and stirred to giveCompound 1 isethionate.

The solid product was confirmed as a crystalline solid according to XRPDanalysis. The XRPD pattern of Compound 1 isethionate is shown in FIG. 30and the peak data is given below in Table 22.

TABLE 22 XRPD Data for Compound 1 Isethionate 2-Theta Height I % 6.755.0 17.5 14.9 210.0 66.9 15.5 53.0 16.9 16.7 58.0 18.5 17.7 57.0 18.218.2 77.0 24.5 19.1 314.0 100.0 19.9 110.0 35.0 20.8 143.0 45.5 21.839.0 12.4 22.6 226.0 72.0 23.3 58.0 18.5 24.8 175.0 55.7 25.8 40.0 12.726.4 86.0 27.4 27.4 61.0 19.4 28.0 131.0 41.7 31.0 97.0 30.9 32.9 29.09.2 34.1 49.0 15.6 36.1 71.0 22.6 38.4 52.0 16.6 40.6 41.0 13.1

Compound 1 isethionate exhibits a DSC thermogram having an endothermpeak at a temperature of about 169° C. and an exotherm peak at atemperature of about 212° C. FIG. 31 shows a DSC thermogram of Compound1 isethionate. FIG. 32 shows a TGA thermogram of Compound 1 isethionate.

Example 26 Preparation and Characterization of Compound 11,2-Ethanedisulfonate

1,2-ethanedisulfonic acid (0.5 M in IPA, 0.14 mmol, 0.28 mL, 2.09 eq)was added to a solution of Compound 1 (26.10 mg, 0.067 mmol, 1.0 eq) inthe mixture of DCM (0.5 mL) and methanol (0.5 mL) and stirred to giveCompound 1 1,2-ethanedisulfonate as a solid.

The solid product was confirmed as a crystalline solid according to XRPDanalysis. The XRPD pattern of Compound 1 1,2-ethanedisulfonate is shownin FIG. 33 and the peak data is given below in Table 23.

TABLE 23 XRPD Data for Compound 1 1,2-ethanedisulfonate 2-Theta Height I% 7.9 286.0 42.8 10.5 255.0 38.1 11.9 33.0 4.9 12.9 120.0 17.9 15.7107.0 16.0 16.8 42.0 6.3 17.6 72.0 10.8 18.4 566.0 84.6 19.4 47.0 7.020.3 152.0 22.7 21.0 235.0 35.1 21.9 104.0 15.5 22.9 78.0 11.7 23.7669.0 100.0 25.0 204.0 30.5 25.8 140.0 20.9 27.1 44.0 6.6 29.0 43.0 6.429.7 34.0 5.1 32.4 43.0 6.4 35.6 77.0 11.5

Compound 1 1,2-ethanedisulfonate exhibits a DSC thermogram having anendotherm peak at a temperature of about 190° C. and an exotherm peak ata temperature of about 221° C. FIG. 34 shows a DSC thermogram ofCompound 1 1,2-ethanedisulfonate.

Example 27 Preparation and Characterization of Compound 1 Mono-Mesylate

Methanesulfonic acid (1.0 M in IPA, 0.14 mmol, 0.14 mL, 2.09 eq) wasadded to a solution of Compound 1 (26.10 mg, 0.067 mmol, 1.0 eq) in themixture of DCM (0.5 mL) and methanol (0.5 mL) and stirred to giveCompound 1 mono-mesylate.

The solid product was confirmed as a crystalline solid according to XRPDanalysis. The XRPD pattern of Compound 1 mono-mesylate is shown in FIG.35 and the peak data is given below in Table 24.

TABLE 24 XRPD Data for Compound 1 Mono-Mesylate 2-Theta Height I % 4.7195.0 35.1 9.5 146.0 26.3 12.4 151.0 27.2 14.5 289.0 52.0 15.9 226.040.6 16.6 287.0 51.6 17.8 93.0 16.7 18.6 220.0 39.6 19.2 151.0 27.2 20.8461.0 82.9 21.8 556.0 100.0 22.6 444.0 79.9 24.6 304.0 54.7 25.1 100.018.0 27.9 59.0 10.6 29.0 103.0 18.5 31.0 95.0 17.1 32.3 40.0 7.2 34.267.0 12.1 35.6 47.0 8.5 38.0 51.0 9.2 39.9 102.0 18.3

Compound 1 mono-mesylate exhibits a DSC thermogram having an endothermpeak at a temperature of about 187° C. FIG. 36 shows a DSC thermogram ofCompound 1 mono-mesylate.

Example 28 Preparation of Compound 1 Sulfate

Sulfuric acid (1.0 M in IPA, fresh prepared, 0.14 mmol, 0.14 mL, 2.09eq) was added dropwise to Compound 1 (26.10 mg, 0.067 mmol, 1.0 eq) inthe mixture of DCM (0.5 mL) and methanol (0.5 mL) and stirred to giveCompound 1 sulfate as an amorphous solid.

Example A LSD1 Histone Demethylase Biochemical Assay

LANCE LSD1/KDM1A demethylase assay-10 μL of 1 nM LSD-1 enzyme (ENZOBML-SE544-0050) in the assay buffer (50 mM Tris, pH 7.5, 0.01% Tween-20,25 mM NaCl, 5 mM DTT) were preincubated for 1 hour at 25° C. with 0.8 μLcompound/DMSO dotted in black 384 well polystyrene plates. Reactionswere started by addition of 10 μL of assay buffer containing 0.4 μMBiotin-labeled Histone H3 peptide substrate:ART-K(Me1)-QTARKSTGGKAPRKQLA-GGK(Biotin) SEQ ID NO:1 (AnaSpec 64355) andincubated for 1 hour at 25° C. Reactions were stopped by addition of 10μL 1× LANCE Detection Buffer (PerkinElmer CR97-100) supplemented with1.5 nM Eu-anti-unmodified H3K4 Antibody (PerkinElmer TRF0404), and 225nM LANCE Ultra Streptavidin (PerkinElmer TRF102) along with 0.9 mMTranylcypromine-HCl (Millipore 616431). After stopping the reactionsplates were incubated for 30 minutes and read on a PHERAstar FS platereader (BMG Labtech). Compounds having an IC₅₀ of 1 μM or less wereconsidered active.

Compound 1 has an IC₅₀ that is ≤100 nM.

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference, including all patent,patent applications, and publications, cited in the present applicationis incorporated herein by reference in its entirety.

What is claimed is:
 1. A salt which is a hydrochloric acid salt of acompound having the structure:


2. The salt of claim 1, wherein the salt is a solid form.
 3. The salt ofclaim 1, wherein the salt is crystalline.
 4. The salt of claim 1,wherein the hydrochloric acid salt is a mono-hydrochloric acid salt. 5.The salt of claim 1, wherein the hydrochloric acid salt is adi-hydrochloric acid salt.
 6. The salt of claim 5, wherein thedi-hydrochloric acid salt is a solid form, which is Form I.
 7. The saltof claim 6, wherein Form I has an X-ray diffraction pattern comprisingat least one characteristic peak in degrees 2θ selected from about 5.9°,about 7.1°, and about 9.9°.
 8. The salt of claim 6, wherein Form I hasan X-ray diffraction pattern comprising at least four characteristicpeaks in degrees 2θ selected from about 5.9°, about 7.1°, about 9.9°,about 13.2°, about 15.1°, and about 18.2°.
 9. The salt of claim 6,wherein Form I has an XRPD pattern with characteristic peakssubstantially shown in FIG.
 1. 10. The salt of claim 6, having a DSCthermogram characterized by endotherm peaks at temperatures of about 80°C. and about 175° C.
 11. The salt of claim 6, having a DSC thermogramsubstantially as shown in FIG.
 2. 12. The salt of claim 6, having a TGAthermogram substantially as shown in FIG.
 3. 13. The salt of claim 5,wherein the di-hydrochloric acid salt is a solid form, which is Form II.14. The salt of claim 13, wherein Form II has an X-ray diffractionpattern comprising at least one characteristic peak in degrees 2θselected from about 5.8°, about 13.2°, and about 15.1°.
 15. The salt ofclaim 13, wherein Form II has an X-ray diffraction pattern comprising atleast four characteristic peaks in degrees 2θ selected from about 5.8°,about 13.2°, about 15.1°, about 17.1°, about 20.1° and about 20.8°. 16.The salt of claim 13, wherein Form II has an XRPD pattern withcharacteristic peaks substantially shown in FIG.
 4. 17. The salt ofclaim 13, having a DSC thermogram having an exotherm peak at atemperature of about 198° C.
 18. The salt of claim 13, having a DSCthermogram substantially as shown in FIG.
 5. 19. The salt of claim 13,having a TGA thermogram substantially as shown in FIG.
 6. 20. The saltof claim 5, wherein the di-hydrochloric acid salt is a solid form, whichis Form
 21. The salt of claim 20, wherein Form III has an X-raydiffraction pattern comprising at least four characteristic peaks indegrees 2θ selected from about 5.4°, about 16.8°, about 21.9°, about27.7°, and about 28.6°.
 22. The salt of claim 5, wherein thedi-hydrochloric acid salt is a solid form, which is Form IV.
 23. Thesalt of claim 22, wherein Form IV has an X-ray diffraction patterncomprising at least four characteristic peaks in degrees 2θ selectedfrom about 5.8°, about 17.4°, about 18.3°, about 20.9°, about 22.5°, andabout 26.9°.
 24. The salt of claim 5, wherein the di-hydrochloric acidsalt is a solid form, which is Form V.
 25. The salt of claim 24, whereinForm V has an X-ray diffraction pattern comprising at least fourcharacteristic peaks in degrees 2θ selected from about 5.4°, about 6.8°,about 13.1°, about 15.2, and about 21.7°.
 26. The salt of claim 4,wherein the mono-hydrochloric acid salt is crystalline.
 27. The salt ofclaim 26, wherein the mono-hydrochloric acid salt has an X-raydiffraction pattern comprising at least four characteristic peaks indegrees 2θ selected from about 10.3°, about 12.8°, about 15.6°, about16.4°, about 21.5°, and about 25.7°.
 28. A salt selected from:3-(cyanomethyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamidemono-methanesulfonic acid salt;3-(cyanomethyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamidedi-methanesulfonic acid salt;3-(cyanomethyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamidemono-malonic acid salt;3-(cyanomethyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamidemono-ethanesulfonic acid salt;3-(cyanomethyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamidemono-maleic acid salt;3-(cyanomethyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamidemono-camphorsulfonic acid salt;3-(cyanomethyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamidemono-isethionic acid salt;3-(cyanomethyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamidemono-1,2-ethanedisulfonic acid salt; and3-(cyanomethyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamidesulfuric acid salt, or a hydrate or solvate thereof.
 29. A process forpreparing Compound 1 having the formula:

or a salt thereof, comprising: deprotecting Compound 2 having theformula:

with A1, wherein A1 is an acid.
 30. The process of claim 29, wherein A1is hydrochloric acid.
 31. The process of claim 29, wherein the processforms Compound 1 di-hydrochloric acid salt.
 32. The process of claim 29,wherein the deprotecting is performed in the presence of S1, wherein S1is a protic solvent.
 33. The process of claim 32, wherein S1 ismethanol.
 34. The process of claim 29, wherein the deprotectingcomprises using about 1 to about 15 molar equivalents of A1 relative toCompound
 2. 35. The process of claim 29, further comprisingprecipitating Compound 1 from a solution comprising Compound 1 and S2,wherein S2 comprises a solvent and an anti-solvent.
 36. The process ofclaim 29, wherein Compound 2 is produced by a process comprising:contacting Compound 3 having the formula:

with Compound 4 having the formula:


37. The process of claim 36, wherein Compound 3 is produced by a processcomprising: treating Compound 5 having the formula:

with B1, wherein B1 is a base.
 38. The process of claim 37, wherein B1is a metal hydroxide base.
 39. The process of claim 37, wherein B1 isKOH.
 40. The process of claim 37, wherein Compound 5 is produced by aprocess comprising: reacting Compound 6 having the formula:

with di-tert-butyl dicarbonate.
 41. The process of claim 40, whereinCompound 6 is produced by a process comprising: contacting Compound 7having the formula:

with Compound 8 having the formula:

in the presence of A2 and RA1, wherein A2 is an acid and RA1 is areducing agent.
 42. The process of claim 41, wherein A2 is an organicacid.
 43. The process of claim 41, wherein A2 is acetic acid.
 44. Theprocess of claim 41, wherein Compound 7 is produced by a processcomprising contacting piperidin-4-one hydrochloride hydrate with2,2,2-trifluoroacetic anhydride in the presence of B2, wherein B2 is abase.
 45. The process of claim 44, wherein B2 is an amine base.
 46. Theprocess of claim 44, wherein B2 is triethylamine.
 47. The process ofclaim 36, wherein Compound 4 is produced by a process comprising:treating Compound 9 having the formula:

with A3, wherein A3 is an acid.
 48. The process of claim 47, wherein A3is an organic acid.
 49. The process of claim 47, wherein A3 istrifluoroacetic acid.
 50. A process for preparing Compound 1 having theformula:

or a salt thereof, comprising: deprotecting Compound 12 having theformula:

with A4, wherein A4 is an acid.
 51. The process of claim 50, wherein thesalt of Compound 1 is a hydrochloric acid salt.
 52. A compound havingthe formula:

or a salt thereof.
 53. A process for preparing a compound of claim 52comprising contacting Compound 13 having the formula:

with di-tert-butyl dicarbonate.
 54. A process for preparing a compoundof claim 53, comprising contacting Compound 3 having the formula:

with Compound 9 having the formula:

in the presence of B4, wherein B4 is a base.
 55. A compound having theformula:

or a salt thereof.
 56. A compound having the formula:

or a salt thereof.
 57. A pharmaceutical composition comprising a salt ofclaim 1, and a pharmaceutically acceptable carrier or excipient.
 58. Apharmaceutical composition comprising a salt of claim 28 or a hydrate orsolvate thereof, and a pharmaceutically acceptable carrier or excipient.59. A solid oral dosage form comprising the pharmaceutical compositionof claim
 57. 60. A solid oral dosage form comprising the pharmaceuticalcomposition of claim
 58. 61. A method of inhibiting LSD1, said methodcomprising: contacting LSD1 with a salt of claim
 1. 62. A method ofinhibiting LSD1, said method comprising: contacting LSD1 with a salt ofclaim 28 or a hydrate or solvate thereof.